|
1
|
Chen X, Xia Y, Min M, Qin L, Liu Y. Optimal dose of bone marrow mesenchymal stem cell transplantation for experimental ulcerative colitis. Regen Ther 2025; 29:177-183. [PMID: 40225050 PMCID: PMC11986536 DOI: 10.1016/j.reth.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/09/2025] [Accepted: 01/19/2025] [Indexed: 04/15/2025] Open
Abstract
Objective To investigate the optimal dose of bone marrow mesenchymal stem cell-transplantation for the ulcerative colitis rat. Methods The BMSC of SD rat were isolated, cultured and labelled with DAPI. SD rats were randomly distributed into 3 groups, Colitis was induced with immune-combined TNBS/ethanol in group A、B、C, 3 groups received caudal vein injection of 1 mL fluids, which contain cell number 1 × 106、5 × 106、1 × 107 separately. 5 rats in each group were sacrificed at day 7 and 14 after injection, Cryostat sections of gut, The number of BMSCs in colon and normal tissue surrounded was observed with fluorescent microscope. Results The DAPI marked BMSCs could been seen in the colic mucosa in each group on day 7、14, more cells in colon than the surrounding normal tissue, compared with 1 × 106 group, More cells in 5 × 106 group (P < 0.05), there were no significant difference (P > 0.05) between 5 × 106 group and 1 × 107 group. There were more cells in colon on 14 day than 7 day, and less in the surrounding normal tissue on 14 day than 7 day. Conclusions The density 5 × 106 is proper of bone mesenchymal stem cells for treatment of ulcerative colitis.
Collapse
Affiliation(s)
- Xiaoyun Chen
- Department of Pathology, Wuhan No.1 Hospital, Wuhan, 430030, China
| | - Yan Xia
- School of Biomedical Engineering and Medical Imaging, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Min Min
- School of Clinical Medicine, School of Medicine, Hubei University of Science and Technology, Xianning, 437100, China
| | - Lingzhi Qin
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yangsheng Liu
- Department of Neurology, Xianning First People's Hospital, Zhongnan Hospital of Wuhan University, Xianning Hospital, Xianning, 437100, China
| |
Collapse
|
|
2
|
Kim M, Kong D, Kim NG, Kim MJ, Kim HY, Choi JJ, Choi YS, Lee HE, Farzaneh KS, Kwon D, Lee S, Kang KS. Therapeutic effect of long-interval repeated subcutaneous administration of canine amniotic membrane-derived mesenchymal stem cells in atopic dermatitis mouse model. BMC Vet Res 2025; 21:115. [PMID: 40011929 PMCID: PMC11866708 DOI: 10.1186/s12917-025-04554-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 01/31/2025] [Indexed: 02/28/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic and inflammatory disease. According to a recent study, administration of canine MSCs is a potential therapy for immunological diseases. However, most related studies involve short-term experiments and acute atopic dermatitis animal models. Thus, studies of repeated subcutaneous injection of canine MSCs for ameliorating long-term inflammatory skin disorders have not yet been established. In this study, we evaluated the effects of long-term canine amniotic mesenchymal stem cells (cAM-MSCs) and calcineurin inhibitors (CNIs) treatments in mouse AD model for up to 8 weeks and compared the differences in therapeutic effect through canine peripheral blood mononuclear cells (PBMCs). Using a mouse model, we validated the therapeutic impact of cAM-MSCs in comparison to pimecrolimus (Pime), the most widely used CNIs, as a therapy for canine AD. Based on our results, we verified that the cAM-MSC treatment group exhibited substantially lower scores for tissue pathologic alterations, inflammatory cytokines, and dermatologic symptoms than the PBS control group. Importantly, compared with Pime, cAM-MSCs were more effective at preventing wound dysfunction and regulating mast cell activity. Additionally, we confirmed that immune modulation proteins (TGF-β1, IDO1, and COX-2) were increased in the cAM-MSCs treatment group. Furthermore, we examined the immunoregulatory effect of cAM-MSCs through the proliferation of T lymphocytes from activated canine PBMCs. As a result, cAM-MSCs suppressed the proliferative capacity of effector T cells from canine PBMCs more effectively than Pime. In conclusion, this study suggested that the cAM-MSCS could be an effective canine treatment for long-term canine AD through regeneration and immunomodulation.
Collapse
Affiliation(s)
- Minsoo Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Dasom Kong
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nam Gyo Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Min-Ji Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hee-Yeong Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jung-Ju Choi
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu-Seung Choi
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ha-Eun Lee
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Khaligh Seyedeh Farzaneh
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Dohyung Kwon
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Kyung-Sun Kang
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
| |
Collapse
|
|
3
|
Kim DY, Park MK, Yang HW, Woo SY, Jung HH, Son DS, Choi BY, Suh SW. Effects of Microplastic Accumulation on Neuronal Death After Global Cerebral Ischemia. Cells 2025; 14:241. [PMID: 39996714 PMCID: PMC11853503 DOI: 10.3390/cells14040241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/31/2025] [Accepted: 01/31/2025] [Indexed: 02/26/2025] Open
Abstract
Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to a stroke due to blocked or unstable blood vessels. Global cerebral ischemia (GCI), characterized by an interruption in blood flow, deprives the brain of oxygen and nutrients, producing reactive oxygen species (ROS) that trigger cell death, which kills nerve cells. Microplastics (MPs), tiny environmental pollutants, can enter the human body through contaminated food, water, disposable items, cosmetics, and more. Once in the brain, MPs can increase neuroinflammation by overstimulating inflammatory factors such as microglia. MPs can also damage neurons by scratching myelin and microtubules, slowing signal transduction, causing cognitive impairment, and leading to neuronal death. Furthermore, microtubule damage may result in the release of phosphorylated tau proteins, potentially linked to Alzheimer's disease. We hypothesized that MPs could exacerbate neuroinflammation and microtubule destruction after GCI, leading to increased neuronal death. To test this hypothesis, we administered MPs (0.5 µm) orally at a dose of 50 mg/kg before and after inducing GCI. Staining techniques such as Fluoro-Jade B (FJB), ionized calcium-binding adaptor molecule 1 (Iba-1), cluster of differentiation 68 (CD68), myelin basic protein (MBP), and microtubule-associated protein 2 (MAP2) were used, along with Western blot analysis for interleukin-6 (IL-6), TNF-α, tau-5, and phospho-tau (S396) to evaluate the effects of MPs on neuronal cell death, neuroinflammation, and microtubule destruction. The results showed that MP accumulation significantly increased neuroinflammation, microtubule disruption, and neuronal cell death in the GCI-MP group compared to the GCI-vehicle group. Therefore, this study suggests that MP accumulation in daily life may contribute to the exacerbation of the disease, potentially leading to severe neuronal cell death after GCI.
Collapse
Affiliation(s)
- Dong Yeon Kim
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| | - Min Kyu Park
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| | - Hyun Wook Yang
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| | - Seo Young Woo
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| | - Hyun Ho Jung
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| | - Dae-Soon Son
- Division of Data Science, Data Science Convergence Research Center, Hallym University, Chuncheon 24252, Republic of Korea;
| | - Bo Young Choi
- Institute of Sport Science, Hallym University, Chuncheon 24252, Republic of Korea;
- Department of Physical Education, Hallym University, Chuncheon 24252, Republic of Korea
| | - Sang Won Suh
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (D.Y.K.); (M.K.P.); (H.W.Y.); (S.Y.W.); (H.H.J.)
| |
Collapse
|
|
4
|
Nguyen PT, Seo Y, Ahn JS, Oh SJ, Park HJ, Yu JH, Kim SH, Lee Y, Yang JW, Cho J, Kang MJ, Park JH, Kim HS. De novo interleukin-10 production primed by Lactobacillus sakei CVL-001 amplifies the immunomodulatory abilities of mesenchymal stem cells to alleviate colitis. Biomed Pharmacother 2025; 182:117745. [PMID: 39705909 DOI: 10.1016/j.biopha.2024.117745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/06/2024] [Accepted: 12/08/2024] [Indexed: 12/23/2024] Open
Abstract
Mesenchymal stem cells (MSCs) hold therapeutic promise for treating inflammatory bowel disease (IBD) owing to their immunomodulatory properties. Currently, pre-conditioning strategies with several beneficial agents have been applied to enhance the efficacy of MSCs in treating IBDs. Probiotics are increasingly acknowledged as supplemental therapy for IBD; however, their potential benefits in MSCs-based therapy remain largely unexplored. In this study, we hypothesized that pretreating MSCs with Lactobacillus sakei CVL-001 (L. sakei CVL-001), a representative probiotic strain, could improve their therapeutic effectiveness for IBD. In line with this hypothesis, we noted that pretreatment with L. sakei CVL-001 significantly induced IL-10 secretion in MSCs via the activation of the STAT3 signaling pathway. These primed MSCs reduced pro-inflammatory cytokine production in LPS/IFN-γ-treated macrophages and promoted an M2 phenotype, associated with immunoregulation and tissue repair, in undifferentiated macrophages. In addition, their conditioned media significantly reduced the proliferation capacity of Jurkat T cells and splenocytes, while the neutralization of IL-10 reversed these phenomena. Furthermore, MSCs treated with L. sakei CVL-001 mitigated inflammatory responses and promoted epithelial regeneration, leading to accelerated recovery from disease symptoms and improved survival rates compared to naive MSCs in a DSS-induced colitis mouse model. In conclusion, our findings suggest that probiotics, such as L. sakei CVL-001, can improve the therapeutic efficacy of MSCs for treating IBD.
Collapse
Affiliation(s)
- Phuong Thao Nguyen
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Su-Jeong Oh
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hee-Jeong Park
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jeong Hyun Yu
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Seong Hui Kim
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yunji Lee
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji Won Yang
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jaejin Cho
- Department of Dental Regenerative Biotechnology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
| | - Min-Jung Kang
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Jong-Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Animal Medical Institute, Chonnam National University, Gwangju 61186, Republic of Korea; NODCURE, Inc, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea.
| | - Hyung-Sik Kim
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
| |
Collapse
|
|
5
|
Zhu F, Ji L, Dai K, Deng S, Wang J, Liu C. In situ licensing of mesenchymal stem cell immunomodulatory function via BMP-2 induced developmental process. Proc Natl Acad Sci U S A 2024; 121:e2410579121. [PMID: 39565311 PMCID: PMC11621467 DOI: 10.1073/pnas.2410579121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/21/2024] [Indexed: 11/21/2024] Open
Abstract
The immunomodulatory function of mesenchymal stem cells (MSCs) is plastic and susceptible to resident microenvironment in vivo or inflammatory factors in vitro. We propose a unique method to enhance the immunoregulatory functions of mesenchymal stem cells (MSCs) through an artificially controllable in vivo inflammatory microenvironment generated by biomaterials loaded with BMP-2 that induce bone development. MSCs activated through this method effectively induce M1 macrophage polarization toward the M2 phenotype, promote differentiation of naïve T cells into regulatory T cells, and inhibit the proliferation of activated T cells via prostaglandin E2 (PGE2) secretion. This in vivo licensing not only preserves the immunogenicity of MSCs but also alters DNA methylation patterns, enabling MSCs to exhibit immunoregulatory effects with epigenetic memory. Validation in a mouse colitis model demonstrated their therapeutic efficacy and long-term viability. Furthermore, we found that the material composition influences the inflammatory response during development, with polysaccharide-based biomaterials proving advantageous over protein-based materials in establishing an inflammatory niche conducive to MSC activity. These findings underscore the potential of tissue engineering to create in vivo environments that license MSCs, offering a strategic avenue to enhance MSC-based therapies for addressing significant immune disorders.
Collapse
Affiliation(s)
- Fuwei Zhu
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Luli Ji
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Kai Dai
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Shunshu Deng
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Jing Wang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Changsheng Liu
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| |
Collapse
|
|
6
|
Zhao T, Mu Y, Deng H, Liang K, Zhou F, Lin Q, Cao F, Zhou F, Yang Z. Research hotspots and trends of mesenchymal stem cell-derived extracellular vesicles for drug delivery: a bibliometric and visualization analysis from 2013 to 2023. Front Cell Dev Biol 2024; 12:1412363. [PMID: 39539963 PMCID: PMC11557358 DOI: 10.3389/fcell.2024.1412363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Our study aims to provide a comprehensive overview of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in drug delivery research, focusing on the period between 2013 and 2023. Given the increasing global interest in this field, we utilized bibliometric tools to explore publication trends, key contributors, and thematic research clusters. Methods Data was collected from the Web of Science (WoS) database, and an in-depth bibliometric analysis was conducted using VOSviewer. The analysis encompassed bibliographic coupling, co-citation, co-authorship, and co-occurrence trends, offering a structured insight into global research activity. We also employed Citespace to further analyze thematic clusters in this domain. Results Our analysis revealed a total of 1,045 publications related to MSC-EVs in drug delivery over the past decade, showing a steady increase in research output. China led in publication count, H-index, prolific authors, and research funding, while the United States ranked highest in total citations, average citation counts, and H-index performance. Pharmaceutics emerged as the leading journal by publication volume, with the Journal of Controlled Release having the strongest total link strength. Top institutions driving research included Shanghai Jiao Tong University, Zhejiang University, and Harvard University. VOSviewer analysis identified four major research clusters: tissue engineering, cancer, neurological diseases, and targeted delivery. Citespace analysis refined this further into ten thematic areas, including differentiation, tissue regeneration, and drug resistance. Discussion This bibliometric assessment provides a holistic visualization of the research landscape for MSC-EVs in drug delivery, underlining the significant contributions of China and the United States. Our findings underscore the increasing global importance of MSC-EV research and highlight emerging themes that will likely guide future research directions. The insights from this study offer a foundational framework for identifying nascent frontiers in MSC-EV-based drug delivery.
Collapse
Affiliation(s)
- Tianyuan Zhao
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Yuhao Mu
- School of Medicine, Nankai University, Tianjin, China
| | - Haobin Deng
- Department of Oncology, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Kaini Liang
- School of Biomedical Engineering, Tsinghua University, Beijing, China
| | - Fanfan Zhou
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Qiyuan Lin
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Fuyang Cao
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Feifei Zhou
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Zhen Yang
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| |
Collapse
|
|
7
|
Zhang G, Song D, Ma R, Li M, Liu B, He Z, Fu Q. Artificial mucus layer formed in response to ROS for the oral treatment of inflammatory bowel disease. SCIENCE ADVANCES 2024; 10:eado8222. [PMID: 39058786 PMCID: PMC11277472 DOI: 10.1126/sciadv.ado8222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024]
Abstract
The artificial mucus layer, such as hydrogels, used to repair the damaged intestinal barrier, is a promising treatment for inflammatory bowel disease (IBD). However, the currently reported hydrogel-based artificial barriers are administered via rectal injection, causing unnecessary discomfort to patients. Herein, we report an oral hydrogel precursor solution based on thiol-modified hyaluronic acid (HASH). Owing to the reactive oxygen species (ROS)-responsive gelling behavior, our precursor solution formed an artificial mucus coating over the inflamed regions of the intestines, blocking microbial invasion and reducing abnormally activated immune responses. Notably, HASH also modulated the gut microbiota, including increasing the diversity and enhancing the abundance of short-chain fatty acid-associated bacteria, which play a key role in gut homeostasis. We believe that the ROS-responsive artificial mucus layer is a promising strategy for the oral treatment of IBD.
Collapse
Affiliation(s)
- Guangshuai Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Dandan Song
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Ruilong Ma
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Mo Li
- Liaoning Institute for Drug Control, No. 7 Chongshan West Road, Shenyang 110016, China
| | - Bingyang Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Zhonggui He
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
- Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China
| | - Qiang Fu
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
- Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China
| |
Collapse
|
|
8
|
Shi L, Chen L, Gao X, Sun X, Jin G, Yang Y, Shao Y, Zhu F, Zhou G. Comparison of different sources of mesenchymal stem cells: focus on inflammatory bowel disease. Inflammopharmacology 2024; 32:1721-1742. [PMID: 38615278 DOI: 10.1007/s10787-024-01468-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/22/2024] [Indexed: 04/15/2024]
Abstract
Inflammatory bowel disease (IBD) poses a significant challenge in modern medicine, with conventional treatments limited by efficacy and associated side effects, necessitating innovative therapeutic approaches. Mesenchymal stem cells (MSC) have emerged as promising candidates for IBD treatment due to their immunomodulatory properties and regenerative potential. This thesis aims to explore and compare various sources of MSC and evaluate their efficacy in treating IBD. This study comprehensively analyses MSC derived from multiple sources, including bone marrow, adipose tissue, umbilical cord, and other potential reservoirs. Core elements of this investigation include assessing differences in cell acquisition, immunomodulatory effects, and differentiation capabilities among these MSC sources, as well as comparing their clinical trial outcomes in IBD patients to their therapeutic efficacy in animal models. Through meticulous evaluation and comparative analysis, this thesis aims to elucidate disparities in the efficacy of different MSC sources for IBD treatment, thereby identifying the most promising therapeutic applications. The findings of this study are intended to advance our understanding of MSC biology and offer valuable insights for selecting the most effective MSC sources for personalized IBD therapy. Ultimately, this research endeavor will optimise therapeutic strategies for managing inflammatory bowel disease through the utilization of MSC.
Collapse
Affiliation(s)
- Lihao Shi
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Leilei Chen
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Xizhuang Gao
- Clinical Medical College of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Xufan Sun
- Clinical Medical College of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Guiyuan Jin
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, People's Republic of China
| | - Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, People's Republic of China
| | - Yiming Shao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Fengqin Zhu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Guangxi Zhou
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China.
| |
Collapse
|
|
9
|
Chen Z, Yao MW, Shen ZL, Li SD, Xing W, Guo W, Li Z, Wu XF, Ao LQ, Lu WY, Lian QZ, Xu X, Ao X. Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression. World J Stem Cells 2023; 15:787-806. [PMID: 37700823 PMCID: PMC10494569 DOI: 10.4252/wjsc.v15.i8.787] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/20/2023] [Accepted: 07/24/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear. AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis. METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis. RESULTS Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice. CONCLUSION Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.
Collapse
Affiliation(s)
- Zhuo Chen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
- College of Basic Medical Sciences, Army Medical University, Chongqing 400038, China
| | - Meng-Wei Yao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhi-Lin Shen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shi-Dan Li
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiao-Feng Wu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Luo-Quan Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wen-Yong Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, The South of Shangcai Village, Wenzhou 325005, Zhejiang Province, China
| | - Qi-Zhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiang Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
- Department of Orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse 857000, Tibet Autonomous Region, China.
| |
Collapse
|
|
10
|
Wei S, Li M, Song W, Liu J, Yu S, Wang Y, Zhang M, Du H, Liu Y, Liu H, Fu W, Li B, Chen YG. The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:30. [PMID: 37574502 PMCID: PMC10423710 DOI: 10.1186/s13619-023-00174-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 07/17/2023] [Indexed: 08/15/2023]
Abstract
Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.
Collapse
Affiliation(s)
- Siting Wei
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Meng Li
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Wanlu Song
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Jiaye Liu
- Department of Thyroid and Parathyroid Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shicheng Yu
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Yalong Wang
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Mengxian Zhang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Huijun Du
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Huidong Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Baojie Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuro- Psychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Guangzhou National Laboratory, Guangzhou, 510005, China.
- School of Basic Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
| |
Collapse
|
|
11
|
Zhu W, Chen Q, Li Y, Wan J, Li J, Tang S. HIF-1α-Overexpressing Mesenchymal Stem Cells Attenuate Colitis by Regulating M1-like Macrophages Polarization toward M2-like Macrophages. Biomedicines 2023; 11:biomedicines11030825. [PMID: 36979804 PMCID: PMC10045413 DOI: 10.3390/biomedicines11030825] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/28/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
A modified mesenchymal stem cell (MSC) transplantation is a highly effective and precise treatment for inflammatory bowel disease (IBD), with a significant curative effect. Thus, we aim to examine the efficacy of hypoxia-inducible factor (HIF)–1α-overexpressing MSC (HIF-MSC) transplantation in experimental colitis and investigate the immunity regulation mechanisms of HIF-MSC through macrophages. A chronic experimental colitis mouse model was established using 2,4,6-trinitrobenzene sulfonic acid. HIF-MSC transplantation significantly attenuated colitis in weight loss rate, disease activity index (DAI), colon length, and pathology score and effectively rebuilt the local and systemic immune balance. Macrophage depletion significantly impaired the benefits of HIF-MSCs on mice with colitis. Immunofluorescence analysis revealed that HIF-MSCs significantly decreased the number of M1-like macrophages and increased the number of M2-like macrophages in colon tissues. In vitro, co-culturing with HIF-MSCs significantly decreased the expression of pro-inflammatory factors, C-C chemokine receptor 7 (CCR-7), and inducible nitric oxide synthase (INOS) and increased the expression of anti-inflammatory factors and arginase I (Arg-1) in induced M1-like macrophages. Flow cytometry revealed that co-culturing with HIF-MSCs led to a decrease in the proportions of M1-like macrophages and an increase in that of M2-like macrophages. HIF-MSCs treatment notably upregulated the expression of downstream molecular targets of phosphatidylinositol 3-kinase-γ (PI3K-γ), including HIF-1α and p-AKT/AKT in the colon tissue. A selected PI3K-γ inhibitor, IPI549, attenuated these effects, as well as the effect on M2-like macrophage polarization and inflammatory cytokines in colitis mice. In vitro, HIF-MSCs notably upregulated the expression of C/EBPβ and AKT1/AKT2, and PI3K-γ inhibition blocked this effect. Modified MSCs stably overexpressed HIF-1α, which effectively regulated macrophage polarization through PI3K-γ. HIF-MSC transplantation may be a potentially effective precision therapy for IBD.
Collapse
Affiliation(s)
- Wenya Zhu
- Medical School of Chinese PLA, Beijing 100039, China
- Department of Geriatrics, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
- Department of Gastroenterology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China
| | - Qianqian Chen
- Department of Gastroenterology, The First Medical Center, Chinese PLA General Hospital, Beijing 100039, China
- Correspondence: (Q.C.); (J.W.)
| | - Yi Li
- Department of Gastroenterology, The First Medical Center, Chinese PLA General Hospital, Beijing 100039, China
| | - Jun Wan
- Department of Gastroenterology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China
- Correspondence: (Q.C.); (J.W.)
| | - Jia Li
- Department of Gastroenterology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China
| | - Shuai Tang
- Department of Gastroenterology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China
| |
Collapse
|
|
12
|
Saadh MJ, Mikhailova MV, Rasoolzadegan S, Falaki M, Akhavanfar R, Gonzáles JLA, Rigi A, Kiasari BA. Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy. Eur J Med Res 2023; 28:47. [PMID: 36707899 PMCID: PMC9881387 DOI: 10.1186/s40001-023-01008-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 01/10/2023] [Indexed: 01/28/2023] Open
Abstract
Recently, mesenchymal stem/stromal cells (MSCs) therapy has become an emerging therapeutic modality for the treatment of inflammatory bowel disease (IBD), given their immunoregulatory and pro-survival attributes. MSCs alleviate dysregulated inflammatory responses through the secretion of a myriad of anti-inflammatory mediators, such as interleukin 10 (IL-10), transforming growth factor-β (TGFβ), prostaglandin E2 (PGE2), tumor necrosis factor-stimulated gene-6 (TSG-6), etc. Indeed, MSC treatment of IBD is largely carried out through local microcirculation construction, colonization and repair, and immunomodulation, thus alleviating diseases severity. The clinical therapeutic efficacy relies on to the marked secretion of various secretory molecules from viable MSCs via paracrine mechanisms that are required for gut immuno-microbiota regulation and the proliferation and differentiation of surrounding cells like intestinal epithelial cells (IECs) and intestinal stem cells (ISCs). For example, MSCs can induce IECs proliferation and upregulate the expression of tight junction (TJs)-associated protein, ensuring intestinal barrier integrity. Concerning the encouraging results derived from animal studies, various clinical trials are conducted or ongoing to address the safety and efficacy of MSCs administration in IBD patients. Although the safety and short-term efficacy of MSCs administration have been evinced, the long-term efficacy of MSCs transplantation has not yet been verified. Herein, we have emphasized the illumination of the therapeutic capacity of MSCs therapy, including naïve MSCs, preconditioned MSCs, and also MSCs-derived exosomes, to alleviate IBD severity in experimental models. Also, a brief overview of published clinical trials in IBD patients has been delivered.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Department of Basic Sciences, Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Maria V Mikhailova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Soheil Rasoolzadegan
- Department of Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojgan Falaki
- Department of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roozbeh Akhavanfar
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Amir Rigi
- Department of Nursing, Young Researchers and Elite Club, Zahedan Branch, Azad University, Zahedan, Iran.
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran.
| |
Collapse
|
|
13
|
Pretreated Mesenchymal Stem Cells and Their Secretome: Enhanced Immunotherapeutic Strategies. Int J Mol Sci 2023; 24:ijms24021277. [PMID: 36674790 PMCID: PMC9864323 DOI: 10.3390/ijms24021277] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/24/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) with self-renewing, multilineage differentiation and immunomodulatory properties, have been extensively studied in the field of regenerative medicine and proved to have significant therapeutic potential in many different pathological conditions. The role of MSCs mainly depends on their paracrine components, namely secretome. However, the components of MSC-derived secretome are not constant and are affected by the stimulation MSCs are exposed to. Therefore, the content and composition of secretome can be regulated by the pretreatment of MSCs. We summarize the effects of different pretreatments on MSCs and their secretome, focusing on their immunomodulatory properties, in order to provide new insights for the therapeutic application of MSCs and their secretome in inflammatory immune diseases.
Collapse
|
|
14
|
Izquierdo-Altarejos P, Cabrera-Pastor A, Martínez-García M, Sánchez-Huertas C, Hernández A, Moreno-Manzano V, Felipo V. Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats. J Neuroinflammation 2023; 20:1. [PMID: 36593485 PMCID: PMC9806918 DOI: 10.1186/s12974-022-02688-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFβ levels and membrane expression of TGFβ receptors in hippocampus. This leads to microglia activation and reduced Smad7-IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1β which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFβ in the EVs from MSCs, which activates TGFβ receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7-IkB pathway. This normalizes IL-1β, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.
Collapse
Affiliation(s)
- Paula Izquierdo-Altarejos
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
| | - Andrea Cabrera-Pastor
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain ,grid.476458.c0000 0004 0427 8560Fundación Investigación Hospital Clínico, Instituto de Investigación Sanitaria, INCLIVA, Valencia, Spain
| | - Mar Martínez-García
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
| | - Carlos Sánchez-Huertas
- grid.418274.c0000 0004 0399 600XNeuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain ,grid.466805.90000 0004 1759 6875Laboratory of Bilateral Neural Circuits, Instituto de Neurociencias (CSIC-UMH), Alicante, Spain
| | - Alberto Hernández
- grid.418274.c0000 0004 0399 600XOptical and Confocal Microscopy Service, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Victoria Moreno-Manzano
- grid.418274.c0000 0004 0399 600XNeuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
| |
Collapse
|
|
15
|
Nassar A, Kodi T, Satarker S, Chowdari Gurram P, Upadhya D, SM F, Mudgal J, Nampoothiri M. Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions. Cells 2022; 11:cells11244111. [PMID: 36552875 PMCID: PMC9776935 DOI: 10.3390/cells11244111] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte-neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.
Collapse
Affiliation(s)
- Ajmal Nassar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Triveni Kodi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Dinesh Upadhya
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Fayaz SM
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
- Correspondence:
| |
Collapse
|
|
16
|
Mesenchymal Stem Cells Promote Intestinal Mucosal Repair by Positively Regulating the Nrf2/Keap1/ARE Signaling Pathway in Acute Experimental Colitis. Dig Dis Sci 2022; 68:1835-1846. [PMID: 36459293 DOI: 10.1007/s10620-022-07722-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 10/04/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND/AIMS Mesenchymal stem cells (MSCs) are a type of adult pluripotent stem cell that has anti-inflammatory and immunomodulatory effects, and whose conditioned medium (CM) has also been found to be effective. We used MSC and CM enemas to investigate their ameliorative effects in a mouse model of colitis. METHODS We employed MSCs, CM, and MSCs + ML385 (an inhibitor of Nrf2) in dextran sodium sulfate (DSS)-induced colitis. Mice were sacrificed on day 8, and the effects of MSC or CM treatment on the levels of inflammation and oxidative stress in colonic epithelial cells were evaluated by histological analyses. RESULTS MSCs inhibited inflammatory cell infiltration and proinflammatory cytokine expression in the colon. In addition, MSCs reduced extracellular matrix deposition and maintained the mechanical barrier and permeability of colonic epithelial cells. Mechanistically, MSCs activated Nrf2, which then increased HO-1 and NQO-1 levels and downregulated the expression of Keap1 to suppress reactive oxygen species production and MDA generation, accompanied by increases in components of the enzymatic antioxidant system, including SOD, CAT, GSH-Px, and T-AOC. However, after administering an Nrf2 inhibitor (ML385) to block the Nrf2/Keap1/ARE pathway, we failed to observe protective effects of MSCs in mice with colitis. CM alone also produced some of the therapeutic benefits of MSCs but was not as effective as MSCs. CONCLUSIONS Our data confirmed that MSCs and CM can effectively improve intestinal mucosal repair in experimental colitis and that MSCs can improve this condition by activating the Nrf2/Keap1/ARE pathway.
Collapse
|
|
17
|
Kim SD, Cho KS. Immunomodulatory Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Allergic Airway Disease. LIFE (BASEL, SWITZERLAND) 2022; 12:life12121994. [PMID: 36556359 PMCID: PMC9786036 DOI: 10.3390/life12121994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022]
Abstract
Mesenchymal stem cells (MSCs) have been reported as promising candidates for the treatment of various diseases, especially allergic diseases, as they have the capacity to differentiate into various cells. However, MSCs itself have several limitations such as creating a risk of aneuploidy, difficulty in handling them, immune rejection, and tumorigenicity, so interest in the extracellular vesicles (EVs) released from MSCs are increasing, and many studies have been reported. Previous studies have shown that extracellular vesicles (EVs) produced by MSCs are as effective as the MSCs themselves in suppression of allergic airway inflammation through the suppression of Th2 cytokine production and the induction of regulatory T cells (Treg) expansion. EVs are one of the substances secreted by paracrine induction from MSCs, and because it exerts its effect by delivering contents such as mRNA, microRNA, and proteins to the receptor cell, it can reduce the problems or risks related to stem cell therapy. This article reviews the immunomodulatory properties of MSCs-derived EVs and their therapeutic implications for allergic airway disease.
Collapse
Affiliation(s)
- Sung-Dong Kim
- Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, 179 Gudeok-Ro, Seo-gu, Busan 602-739, Republic of Korea
| | - Kyu-Sup Cho
- Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, 179 Gudeok-Ro, Seo-gu, Busan 602-739, Republic of Korea
| |
Collapse
|
|
18
|
Pozzobon M, D’Agostino S, Roubelakis MG, Cargnoni A, Gramignoli R, Wolbank S, Gindraux F, Bollini S, Kerdjoudj H, Fenelon M, Di Pietro R, Basile M, Borutinskaitė V, Piva R, Schoeberlein A, Eissner G, Giebel B, Ponsaerts P. General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications. Front Bioeng Biotechnol 2022; 10:961987. [PMID: 36263355 PMCID: PMC9574482 DOI: 10.3389/fbioe.2022.961987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
Collapse
Affiliation(s)
- Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Stefania D’Agostino
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Maria G. Roubelakis
- Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, The Research Center in Cooperation with AUVA Trauma Research Center, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et plastique, CHU Besançon, Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, University Bourgogne Franche-Comté, Besançon, France
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Halima Kerdjoudj
- University of Reims Champagne Ardenne, EA 4691 BIOS “Biomatériaux et Inflammation en Site Osseux”, UFR d’Odontologie, Reims, France
| | | | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Mariangela Basile
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Veronika Borutinskaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
| | - Roberta Piva
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Guenther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| |
Collapse
|
|
19
|
Ye Y, Zhang X, Su D, Ren Y, Cheng F, Yao Y, Shi G, Ji Y, Chen S, Shi P, Dai L, Su X, Deng H. Therapeutic efficacy of human adipose mesenchymal stem cells in Crohn's colon fibrosis is improved by IFN-γ and kynurenic acid priming through indoleamine 2,3-dioxygenase-1 signaling. Stem Cell Res Ther 2022; 13:465. [PMID: 36076306 PMCID: PMC9461110 DOI: 10.1186/s13287-022-03157-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/17/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic relapsing-remitting inflammatory diseases of the gastrointestinal tract that are typically categorized into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although MSCs therapy has achieved encouraging outcomes in IBD therapy, objective responses are limited in colon fibrosis stenosis owing to the complicated microenvironment of CD and MSCs heterogeneity of quality. Here, we chose IFN-γ and kynurenic acid (KYNA) to overcome the low response and heterogeneity of human adipose-derived MSCs (hADSCs) to treat IBD and expand the therapeutic effects based on the excellent ability of IFN-γ and KYNA to promote indoleamine 2,3-dioxygenase-1 (IDO-1) signaling, providing a potential protocol to treat IBD and fibrosis disease. METHODS hADSCs were isolated, cultured, and identified from human abdominal adipose tissue. The CD pathology-like acute colitis and chronic colon fibrosis rat model was induced by 2,4,6-trinitrobenzen sulfonic acid (TNBS). hADSCs were pretreated in vitro with IFN-γ and KYNA and then were transplanted intravenously at day 1 and 3 of TNBS administration in colitis along with at day 1, 15, and 29 of TNBS administration in chronic colonic fibrosis. Therapeutic efficacy was evaluated by body weights, disease activity index, pathological staining, real-time PCR, Western blot, and flow cytometry. For knockout of IDO-1, hADSCs were transfected with IDO-1-targeting small gRNA carried on a CRISPR-Cas9-lentivirus vector. RESULTS hADSCs treated with IFN-γ and KYNA significantly upregulated the expression and secretion of IDO-1, which has effectively ameliorated CD pathology-like colitis injury and fibrosis. Notably, the ability of hADSCs with IDO-1 knockout to treat colitis was significantly impaired and diminished the protective effects of the primed hADSCs with IFN-γ and KYNA. CONCLUSION Inflammatory cytokines IFN-γ- and KYNA-treated hADSCs more effectively alleviate TNBS-induced colitis and colonic fibrosis through an IDO-1-dependent manner. Primed hADSCs are a promising new strategy to improve the therapeutic efficacy of MSCs and worth further research.
Collapse
Affiliation(s)
- Yixin Ye
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xiaomei Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Dongsheng Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yushuang Ren
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Fuyi Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunqi Yao
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yanhong Ji
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Shuang Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Pengyi Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China.
| |
Collapse
|
|
20
|
Feng H, Liu Q, Deng Z, Li H, Zhang H, Song J, Liu X, Liu J, Wen B, Wang T. Human umbilical cord mesenchymal stem cells ameliorate erectile dysfunction in rats with diabetes mellitus through the attenuation of ferroptosis. Stem Cell Res Ther 2022; 13:450. [PMID: 36064453 PMCID: PMC9444126 DOI: 10.1186/s13287-022-03147-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Background Erectile dysfunction (ED), as one of the most prevalent consequences in male diabetic patients, has a serious impact on men's physical and mental health, and the treatment effect of diabetic mellitus erectile dysfunction (DMED) is often worse. Therefore, the development of a novel therapeutic approach is urgent. As stem cells with high differentiation potential, human umbilical cord mesenchymal stem cells (HUCMSCs) have been widely used in the treatment of diseases in other systems, and are expected to be a promising strategy for the treatment of DMED. In this study, we investigated the role of HUCMSCs in managing erectile function in rat models of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and compared the effects of two different injection methods. Methods T1DM and T2DM ED rats were given labelled HUCMSCs by corpus cavernosum injection and tail vein injection, respectively. ICP and MAP were monitored simultaneously by electrical stimulation four weeks after injection to indicate the erectile function of rats. To track the development and colonisation capabilities of stem cells, we performed EdU assay with penile tissue. The histological changes of the penis were observed by hematoxylin–eosin staining, and Masson’s trichrome staining was conducted to evaluate the smooth muscle content and the degree of fibrosis in the rat penis. Then, we employed specific kits to measure the level of NO, cGMP, MDA, SOD and Fe in penis. Electron transmission microscopy was implemented to observe morphology of mitochondria. Besides, western blot and immunofluorescence staining were performed to demonstrate the expression of ferroptosis-related genes. Results We found that HUCMSCs improved erectile function in T1DM and T2DM ED rats, with no difference in efficacy between corpus cavernosum injection and tail vein injection. The EdU assay revealed that only a tiny percentage of HUCMSCs colonised the corpus cavernosum, while smooth muscle in the penis expanded and collagen decreased following HUCMSC injection. Moreover, the levels of oxidative stress in the penis of the rats given HUCMSCs were dramatically reduced, as was the tissue iron content. HUCMSCs normalised mitochondrial morphology within corpus cavernosum smooth muscle cells (CCSMCs), which were characteristically altered by high glucose. Furthermore, the expression of ferroptosis inhibitory genes SLC7A11 and GPX4 was obviously elevated in CCSMCs after stem cell management, but the abundances of ACSL4, LPCAT3 and ALOX15 showed the polar opposite tendency. Conclusions HUCMSCs can effectively and safely alleviate erectile dysfunction in T1DM and T2DM ED rats, while restoring erectile function by attenuating diabetes-induced ferroptosis in CCSMCs. Additionally, this study provides significant evidence for the development of HUCMSCs as a viable therapeutic strategy for DMED. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03147-w.
Collapse
Affiliation(s)
- Huan Feng
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qi Liu
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China
| | - Zhiyao Deng
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, Guangdong, China
| | - Hao Li
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huajie Zhang
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China
| | - Jingyu Song
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaming Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jihong Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bo Wen
- Department of Urology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China.
| | - Tao Wang
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. .,Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, Guangdong, China.
| |
Collapse
|
|
21
|
Omar TA, Sweed E, Sweed D, Eledel RH, Abou-Elela DH, Hikal G. Mesenchymal Stem Cells for the Treatment of Acetic Acid-Induced Ulcerative Colitis in Rats. Open Access Maced J Med Sci 2022; 10:1478-1486. [DOI: 10.3889/oamjms.2022.10686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Background: Ulcerative colitis (UC) is an autoimmune inflammatory bowel disease, characterized by chronic and relapsing inflammation of the intestinal mucosa. Clinical treatments fail to reduce inflammation and induce side effects in nearly 30% of patients. Mesenchymal stem cells (MSCs) are immunomodulatory agents that can encourage tissue repair and regeneration.
Aim: To investigate the ability of MSCs to differentiate into enterocytes under the mediation of activin a, fibroblastic growth factor 2, and epidermal growth factors and to study the effect of administering MSCs to rats with acetic acid (AA)-induced UC.
Methods: MSCs isolated from the umbilical cord were induced to differentiate into enterocytes. The induced cells were morphologically evaluated by flow cytometry and immunocytochemistry. Forty rats were divided into four groups: control, AA-induced UC, differentiated, and undifferentiated MSC treated groups. The acute UC in rats was induced by 3% AA transrectal administration. Body weight changes, disease activity index (DAI), and histopathological and immunohistochemical CD105 and CD34 staining were recorded. IL-17, IL-10, and TGF- β levels were measured as well.
Results: In Both differentiated and undifferentiated MSCs, induced MSCs improved the DAI score and significantly recovered the pathological changes. The favorable effect of MSCs was significantly linked to CD105 overexpression and CD34 low expression. IL-10 and TGF-β levels increased while IL-17 levels decreased.
Conclusion: Both differentiated and undifferentiated MSCs showed anti-inflammatory and immunomodulatory effects in our study. Based on our results, MSCs could become potentially useful for regenerative medicine and the clinical treatment of UC.
Collapse
|
|
22
|
Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ. Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges. Int J Mol Sci 2022; 23:ijms23168905. [PMID: 36012170 PMCID: PMC9408403 DOI: 10.3390/ijms23168905] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are an example of chronic diseases affecting 40% of the population, which involved tissue damage and an inflammatory process not satisfactorily controlled with current therapies. Data suggest that mesenchymal stem cells (MSC) may be a therapeutic option for these processes, and especially for IBD, due to their multifactorial approaches such as anti-inflammatory, anti-oxidative stress, anti-apoptotic, anti-fibrotic, regenerative, angiogenic, anti-tumor, or anti-microbial. However, MSC therapy is associated with important limitations as safety issues, handling difficulties for therapeutic purposes, and high economic cost. MSC-derived secretome products (conditioned medium or extracellular vesicles) are therefore a therapeutic option in IBD as they exhibit similar effects to their parent cells and avoid the issues of cell therapy. In this review, we proposed further studies to choose the ideal tissue source of MSC to treat IBD, the implementation of new standardized production strategies, quality controls and the integration of other technologies, such as hydrogels, which may improve the therapeutic effects of derived-MSC secretome products in IBD.
Collapse
Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | | | - Luis O. González
- Department of Anatomical Pathology, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Department of Surgery, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
| |
Collapse
|
|
23
|
Wusiman W, Zhang Z, Ding Q, Liu M. The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases. Front Physiol 2022; 13:935576. [PMID: 36017335 PMCID: PMC9396140 DOI: 10.3389/fphys.2022.935576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/05/2022] [Indexed: 12/24/2022] Open
Abstract
Aminoacyl-tRNA synthetases (ARSs) catalyze the ligation of amino acids to their cognate transfer RNAs and are indispensable enzymes for protein biosynthesis in all the cells. Previously, ARSs were considered simply as housekeeping enzymes, however, they are now known to be involved in a variety of physiological and pathological processes, such as tumorigenesis, angiogenesis, and immune response. In this review, we summarize the role of ARSs in the digestive system, including the esophagus, stomach, small intestine, colon, as well as the auxiliary organs such as the pancreas, liver, and the gallbladder. Furthermore, we specifically focus on the diagnostic and prognostic value of ARSs in cancers, aiming to provide new insights into the pathophysiological implications of ARSs in tumorigenesis.
Collapse
Affiliation(s)
- Wugelanmu Wusiman
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zerui Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Ding
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Mei Liu,
| |
Collapse
|
|
24
|
Guo G, Tan Z, Liu Y, Shi F, She J. The therapeutic potential of stem cell-derived exosomes in the ulcerative colitis and colorectal cancer. Stem Cell Res Ther 2022; 13:138. [PMID: 35365226 PMCID: PMC8973885 DOI: 10.1186/s13287-022-02811-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/23/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) therapy is a novel treatment strategy for cancer and a wide range of diseases with an excessive immune response such as ulcerative colitis (UC), due to its powerful immunomodulatory properties and its capacity for tissue regeneration and repair. One of the promising therapeutic options can focus on MSC-secreted exosomes (MSC-Exo), which have been identified as a type of paracrine interaction. In light of a wide variety of recent experimental studies, the present review aims to seek the recent research advances of therapies based on the MSC-Exo for treating UC and colorectal cancer (CRC). METHODS A systematic literature search in MEDLINE, Scopus, and Google Scholar was performed from inception to December 2021 using the terms [("colorectal cancer" OR "bowel cancer" OR "colon cancer" OR "rectal cancer") AND (exosome) AND (stem cell) AND ("inflammatory bowel disease" OR "Crohn's disease" OR "colitis")] in titles and abstracts. FINDINGS Exosomes derived from various sources of MSCs, including human umbilical cord-derived MSCs (hUC-MSCs), human adipose-derived MSCs (hAD-MSCs), human bone marrow-derived MSCs (hBM-MSCs), and olfactory ecto-MSCs (OE-MSCs), have shown the protective role against UC and CRC. Exosomes from hUC-MSCs, hBM-MSCs, AD-MSCs, and OE-MSCs have been found to ameliorate the experimental UC through suppressing inflammatory cells including macrophages, Th1/Th17 cells, reducing the expression of proinflammatory cytokines, as well as inducing the anti-inflammatory function of Treg and Th2 cells and enhancing the expression of anti-inflammatory cytokines. In addition, hBM-MSC-Exo and hUC-MSC-Exo containing tumor-suppressive miRs (miR-3940-5p/miR-22-3p/miR-16-5p) have been shown to suppress proliferation, migration, and invasion of CRC cells via regulation of RAP2B/PI3K/AKT signaling pathway and ITGA2/ITGA6. KEY MESSAGES The MSC-Exo can exert beneficial effects on UC and CRC through two different mechanisms including modulating immune responses and inducing anti-tumor responses, respectively.
Collapse
Affiliation(s)
- Gang Guo
- Center for Gut Microbiome Research, Med-X Institute Centre, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
- Department of Talent Highland, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
| | - Zhaobang Tan
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, 710032 China
| | - Yaping Liu
- Department of Gastroenterology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
| | - Feiyu Shi
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
| | - Junjun She
- Center for Gut Microbiome Research, Med-X Institute Centre, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
- Department of Talent Highland, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, 710061 China
| |
Collapse
|
|
25
|
Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, Makarem J, Nasiri R, Salahshour F, Dehghan-Manshadi SA, Kazemnejad S. Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II. Stem Cell Res Ther 2022; 13:96. [PMID: 35255966 PMCID: PMC8899458 DOI: 10.1186/s13287-022-02771-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/17/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Cell-free Mesenchymal stromal cells (MSCs) have been considered due to their capacity to modulate the immune system and suppress cytokine storms caused by SARS-CoV-2. This prospective randomized double-blind placebo-controlled clinical trial aimed to assess the safety and efficacy of secretome derived from allogeneic menstrual blood stromal cells (MenSCs) as a treatment in patients with severe COVID-19. METHODS Patients with severe COVID-19 were randomized (1:1) to either MenSC-derived secretome treatment or the control group. Subjects received five intravenous infusions of 5 mL secretome or the same volume of placebo for five days and were monitored for safety and efficacy for 28 days after treatment. Adverse events, laboratory parameters, duration of hospitalization, clinical symptom improvement, dynamic of O2 saturation, lymphocyte number, and serial chest imaging were analyzed. RESULTS All safety endpoints were observed without adverse events after 72 h of secretome injection. Within 28 days after enrollment, 7 patients (50%) were intubated in the treated group versus 12 patients (80%) in the control group. Overall, 64% of patients had improved oxygen levels within 5 days of starting treatment (P < 0.0001) and there was a survival rate of 57% in the treatment group compared to 28% in the control group was (P < 0.0001). Laboratory values revealed that significant acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. Significant improvement in lymphopenia was associated with an increase in mean CD4+ and CD8+ lymphocyte counts of 20% (P = 0.06) and 15% (P < 0.05), respectively. Following treatment, percentage of pulmonary involvement showed a significant improvement in the secretome group (P < 0.0001). This improvement differed significantly between survivors and those who were dying (P < 0.005). CONCLUSIONS For the first time, this study demonstrated that in hospitalized patients with severe COVID-19, therapy with MenSCs-derived secretome leads to reversal of hypoxia, immune reconstitution, and downregulation of cytokine storm, with no adverse effects attributable to the treatment. Given these outcomes, it may be possible to use this type of treatment for serious inflammatory lung disease with a mechanism similar to COVID-19 in the future. However, it is necessary to evaluate the safety and efficacy of MenSCs-derived secretome therapy in clinical trials on a larger population of patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05019287. Registered 24AGUEST 2021, retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT05019287 . IRCT, IRCT20180619040147N6. Registered 04/01/2021.
Collapse
Affiliation(s)
- Mina Fathi-Kazerooni
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Samrand Fattah-Ghazi
- Department of Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Darzi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Jalil Makarem
- Department of Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Nasiri
- Avicenna Fertility Clinic, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Faeze Salahshour
- Department of Radiology, Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran.,Liver Transplantation Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Ali Dehghan-Manshadi
- Department of Infectious Diseases and Tropical Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
| |
Collapse
|
|
26
|
Nazari H, Naei VY, Tabasi AH, Badripour A, Akbari Asbagh R, Keramati MR, Sharifi A, Behboudi B, Kazemeini A, Abbasi M, Keshvari A, Ahmadi Tafti SM. Advanced Regenerative Medicine Strategies for Treatment of Perianal Fistula in Crohn's Disease. Inflamm Bowel Dis 2022; 28:133-142. [PMID: 34291798 DOI: 10.1093/ibd/izab151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Indexed: 12/15/2022]
Abstract
Regenerative medicine is an emerging therapeutic method that aims to reconstruct tissues and organs. This advanced therapeutic approach has demonstrated great potential in addressing the limitations of medical and surgical procedures for treating perineal fistula in patients with Crohn's disease. Recent developments in stem cell technology have led to a massive good manufacturing practices (GMPs) production of various stem cells, including mesenchymal and embryonic cells, along with induction of pluripotent stem cells to repair damaged tissues in the fistula. The recent advances in separation and purification of exosomes, as biologic nanovesicles carrying anti-inflammatory and regenerative agents, have made them powerful tools to treat this inflammatory disease. Further, tremendous advances in nanotechnology, biomaterials, and scaffold fabrication methods enable tissue engineering methods to synthesize tissue-like structures to assist surgical techniques. This review focuses on advanced regenerative-based methods including stem cell therapy, exosome therapy, and tissue engineering used in the treatment of perianal fistula. Relevant in vitro and in vivo studies and the latest innovations in implementation of regenerative medicine for this disease are also separately reviewed. Additionally, current challenges regarding implementation of g stem cells, exosomes, and tissue engineering methods for bridging the gaps between laboratory findings and clinic application will be discussed.
Collapse
Affiliation(s)
- Hojjatollah Nazari
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Yaghoubi Naei
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Asieh Heirani Tabasi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Department of Cell Therapy and Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abolfazl Badripour
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Akbari Asbagh
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Keramati
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirsina Sharifi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Behboudi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Kazemeini
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Amir Keshvari
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Ahmadi Tafti
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
27
|
Kulus M, Sibiak R, Stefańska K, Zdun M, Wieczorkiewicz M, Piotrowska-Kempisty H, Jaśkowski JM, Bukowska D, Ratajczak K, Zabel M, Mozdziak P, Kempisty B. Mesenchymal Stem/Stromal Cells Derived from Human and Animal Perinatal Tissues-Origins, Characteristics, Signaling Pathways, and Clinical Trials. Cells 2021; 10:cells10123278. [PMID: 34943786 PMCID: PMC8699543 DOI: 10.3390/cells10123278] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are currently one of the most extensively researched fields due to their promising opportunity for use in regenerative medicine. There are many sources of MSCs, of which cells of perinatal origin appear to be an invaluable pool. Compared to embryonic stem cells, they are devoid of ethical conflicts because they are derived from tissues surrounding the fetus and can be safely recovered from medical waste after delivery. Additionally, perinatal MSCs exhibit better self-renewal and differentiation properties than those derived from adult tissues. It is important to consider the anatomy of perinatal tissues and the general description of MSCs, including their isolation, differentiation, and characterization of different types of perinatal MSCs from both animals and humans (placenta, umbilical cord, amniotic fluid). Ultimately, signaling pathways are essential to consider regarding the clinical applications of MSCs. It is important to consider the origin of these cells, referring to the anatomical structure of the organs of origin, when describing the general and specific characteristics of the different types of MSCs as well as the pathways involved in differentiation.
Collapse
Affiliation(s)
- Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Rafał Sibiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Division of Reproduction, Department of Obstetrics, Gynecology, and Gynecologic Oncology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
| | - Maciej Zdun
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Maria Wieczorkiewicz
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Hanna Piotrowska-Kempisty
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
| | - Jędrzej M. Jaśkowski
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Kornel Ratajczak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Maciej Zabel
- Division of Anatomy and Histology, University of Zielona Gora, 65-046 Zielona Gora, Poland;
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Correspondence:
| |
Collapse
|
|
28
|
Improving the Efficacy of Mesenchymal Stem/Stromal-Based Therapy for Treatment of Inflammatory Bowel Diseases. Biomedicines 2021; 9:biomedicines9111507. [PMID: 34829736 PMCID: PMC8615066 DOI: 10.3390/biomedicines9111507] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) consisting of persistent and relapsing inflammatory processes of the intestinal mucosa are caused by genetic, environmental, and commensal microbiota factors. Despite recent advances in clinical treatments aiming to decrease inflammation, nearly 30% of patients treated with biologicals experienced drawbacks including loss of response, while others can develop severe side effects. Hence, novel effective treatments are highly needed. Mesenchymal stem/stromal cell (MSCs) therapy is an innovative therapeutic alternative currently under investigation for IBD. MSCs have the inherent capacity of modulating inflammatory immune responses as well as regenerating damaged tissues and are therefore a prime candidate to use as cell therapy in patients with IBD. At present, MSC-based therapy has been shown preclinically to modulate intestinal inflammation, whilst the safety of MSC-based therapy has been demonstrated in clinical trials. However, the successful results in preclinical studies have not been replicated in clinical trials. In this review, we will summarize the protocols used in preclinical and clinical trials and the novel approaches currently under investigation which aim to increase the beneficial effects of MSC-based therapy for IBD.
Collapse
|
|
29
|
Shin N, Jung N, Lee SE, Kong D, Kim NG, Kook MG, Park H, Choi SW, Lee S, Kang KS. Pimecrolimus interferes the therapeutic efficacy of human mesenchymal stem cells in atopic dermatitis by regulating NFAT-COX2 signaling. Stem Cell Res Ther 2021; 12:482. [PMID: 34454603 PMCID: PMC8399851 DOI: 10.1186/s13287-021-02547-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/08/2021] [Indexed: 11/10/2022] Open
Abstract
Background Human mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug–cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD. Methods hUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus. Results Pimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE2, one of the most critical immunomodulatory factors in hUCB-MSCs. And we demonstrated that pimecrolimus downregulated COX2-PGE2 axis by inhibiting nuclear translocation of NFAT3. Conclusions Coadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02547-8.
Collapse
Affiliation(s)
- Nari Shin
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Namhee Jung
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Seung-Eun Lee
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Dasom Kong
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Nam Gyo Kim
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Myung Geun Kook
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Hwanhee Park
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Soon Won Choi
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea.
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
| |
Collapse
|
|
30
|
Bucar S, Branco ADDM, Mata MF, Milhano JC, Caramalho Í, Cabral JMS, Fernandes-Platzgummer A, da Silva CL. Influence of the mesenchymal stromal cell source on the hematopoietic supportive capacity of umbilical cord blood-derived CD34 +-enriched cells. Stem Cell Res Ther 2021; 12:399. [PMID: 34256848 PMCID: PMC8278708 DOI: 10.1186/s13287-021-02474-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/24/2021] [Indexed: 12/18/2022] Open
Abstract
Background Umbilical cord blood (UCB) is a clinically relevant alternative source of hematopoietic stem/progenitor cells (HSPC). To overcome the low cell number per UCB unit, ex vivo expansion of UCB HSPC in co-culture with mesenchymal stromal cells (MSC) has been established. Bone marrow (BM)-derived MSC have been the standard choice, but the use of MSC from alternative sources, less invasive and discardable, could ease clinical translation of an expanded CD34+ cell product. Here, we compare the capacity of BM-, umbilical cord matrix (UCM)-, and adipose tissue (AT)-derived MSC, expanded with/without xenogeneic components, to expand/maintain UCB CD34+-enriched cells ex vivo. Methods UCB CD34+-enriched cells were isolated from cryopreserved mononuclear cells and cultured for 7 days over an established feeder layer (FL) of BM-, UCM-, or AT-derived MSC, previously expanded using fetal bovine serum (FBS) or fibrinogen-depleted human platelet lysate (HPL) supplemented medium. UCB cells were cultured in serum-free medium supplemented with SCF/TPO/FLT3-L/bFGF. Fold increase in total nucleated cells (TNC) as well as immunophenotype and clonogenic potential (cobblestone area-forming cells and colony-forming unit assays) of the expanded hematopoietic cells were assessed. Results MSC from all sources effectively supported UCB HSPC expansion/maintenance ex vivo, with expansion factors (in TNC) superior to 50x, 70x, and 80x in UCM-, BM-, and AT-derived MSC co-cultures, respectively. Specifically, AT-derived MSC co-culture resulted in expanded cells with similar phenotypic profile compared to BM-derived MSC, but resulting in higher total cell numbers. Importantly, a subpopulation of more primitive cells (CD34+CD90+) was maintained in all co-cultures. In addition, the presence of a MSC FL was essential to maintain and expand a subpopulation of progenitor T cells (CD34+CD7+). The use of HPL to expand MSC prior to co-culture establishment did not influence the expansion potential of UCB cells. Conclusions AT represents a promising alternative to BM as a source of MSC for co-culture protocols to expand/maintain HSPC ex vivo. On the other hand, UCM-derived MSC demonstrated inferior hematopoietic supportive capacity compared to MSC from adult tissues. Despite HPL being considered an alternative to FBS for clinical-scale manufacturing of MSC, further studies are needed to determine its impact on the hematopoietic supportive capacity of these cells.
Collapse
Affiliation(s)
- Sara Bucar
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - André Dargen de Matos Branco
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Márcia F Mata
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - João Coutinho Milhano
- Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
| | | | - Joaquim M S Cabral
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal. .,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
| |
Collapse
|
|
31
|
Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids. Int J Mol Sci 2021; 22:ijms22126431. [PMID: 34208517 PMCID: PMC8233984 DOI: 10.3390/ijms22126431] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 01/08/2023] Open
Abstract
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.
Collapse
|
|
32
|
Regmi S, Seo Y, Ahn JS, Pathak S, Acharya S, Nguyen TT, Yook S, Sung JH, Park JB, Kim JO, Young CS, Kim HS, Jeong JH. Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration. Biomaterials 2021; 271:120752. [PMID: 33730631 DOI: 10.1016/j.biomaterials.2021.120752] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/02/2021] [Indexed: 12/15/2022]
Abstract
Tissue repairing capacity and immunomodulatory effects of mesenchymal stem cells (MSCs) have been extensively utilized for treating various inflammatory disorders; however, inconsistent efficacy and therapeutic outcomes due to low survival rate after transplantation often restrain their clinical potential. To overcome these limitations, 3-dimensional culture (3D-culture) was established to augment stemness and paracrine functions of MSCs, although hypoxic stress at the core often leads to unexpected cell death. Thus, we designed a novel strategy to improve the microenvironment of MSCs by creating heterospheroids (HS) consisting of MSCs and quercetin (QUR)-loaded microspheres (MSCHS), to achieve local drug delivery to the cells. Notably, MSCHS exhibited resistance for senescence-associated phenotype and oxidative stress-induced apoptosis compared to 3D-cultured MSCs (MSC3D), as well as to 2D-cultured cells (MSC2D) in vitro. In a murine model of colitis, MSC3D and MSCHS exhibited enhanced anti-inflammatory impact than MSC2Dvia attenuating neutrophil infiltration and regulating helper T cell (Th) polarization into Th1 and Th17 cells. Interestingly, MSCHS provided better therapeutic outcomes compared to MSC3D, partially due to their enhanced survival capacity in vivo. Moreover, we found that MSC-derived paracrine factor, prostaglandin E2 (PGE2), can directly drive the epithelial regeneration process by inducing specialized tissue-repairing cell generation using the intestinal organoid culture. Importantly, MSC3D and MSCHS displayed an outstanding regeneration-inducing potency compared to MSC2D owing to their superior PGE2 secretion. Taken together, we suggest a convergent strategy of MSCHS formation with reactive oxygen species (ROS) scavenger, QUR, which can maximize the inflammation-attenuating and tissue-repairing capacity of MSCs, as well as the engraftment efficiency after transplantation.
Collapse
Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea; Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Yoojin Seo
- School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea; Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Ji-Su Ahn
- School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea; Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea; Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Suman Acharya
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Tiep Tien Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea; STEMORE Co. Ltd., Incheon 21983, Republic of Korea
| | - Jun-Beom Park
- Department of Periodontics, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Chul Soon Young
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Hyung-Sik Kim
- School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea; Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
| |
Collapse
|
|
33
|
Regulatory Effect of Mesenchymal Stem Cells on T Cell Phenotypes in Autoimmune Diseases. Stem Cells Int 2021; 2021:5583994. [PMID: 33859701 PMCID: PMC8024100 DOI: 10.1155/2021/5583994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Research on mesenchymal stem cells (MSCs) starts from the earliest assumption that cells derived from the bone marrow have the ability to repair tissues. Several scientists have since documented the crucial role of bone marrow-derived MSCs (BM-MSCs) in processes such as embryonic bone and cartilage formation, adult fracture and tissue repair, and immunomodulatory activities in therapeutic applications. In addition to BM-MSCs, several sources of MSCs have been reported to possess tissue repair and immunoregulatory abilities, making them potential treatment options for many diseases. Therefore, the therapeutic potential of MSCs in various diseases including autoimmune conditions has been explored. In addition to an imbalance of T cell subsets in most patients with autoimmune diseases, they also exhibit complex disease manifestations, overlapping symptoms among diseases, and difficult treatment. MSCs can regulate T cell subsets to restore their immune homeostasis toward disease resolution in autoimmune conditions. This review summarizes the role of MSCs in relieving autoimmune diseases via the regulation of T cell phenotypes.
Collapse
|
|
34
|
Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22073397. [PMID: 33806241 PMCID: PMC8037333 DOI: 10.3390/ijms22073397] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been developed as cell therapeutics for various immune disorders using their immunoregulatory properties mainly exerted by their paracrine functions. However, variation among cells from different donors, as well as rapid clearance after transplantation have impaired the uniform efficacy of MSCs and limited their application. Recently, several strategies to overcome this limitation have been suggested and proven in pre-clinical settings. Therefore, in this review article, we will update the knowledge on bioengineering strategies to improve the immunomodulatory functions of MSCs, including genetic modification and physical engineering.
Collapse
|
|
35
|
Chen J, Zheng CX, Jin Y, Hu CH. Mesenchymal stromal cell-mediated immune regulation: A promising remedy in the therapy of type 2 diabetes mellitus. STEM CELLS (DAYTON, OHIO) 2021; 39:838-852. [PMID: 33621403 DOI: 10.1002/stem.3357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/03/2021] [Indexed: 11/09/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a major threat to global public health, with increasing prevalence as well as high morbidity and mortality, to which immune dysfunction has been recognized as a crucial contributor. Mesenchymal stromal cells (MSCs), obtained from various sources and possessing potent immunomodulatory abilities, have displayed great therapeutic potential for T2DM. Interestingly, the immunomodulatory capabilities of MSCs are endowed and plastic. Among the multiple mechanisms involved in MSC-mediated immune regulation, the paracrine effects of MSCs have attracted much attention. Of note, extracellular vesicles (EVs), an important component of MSC secretome, have emerged as pivotal mediators of their immunoregulatory effects. Particularly, the necrobiology of MSCs, especially apoptosis, has recently been revealed to affect their immunomodulatory functions in vivo. In specific, a variety of preclinical studies have demonstrated the beneficial effects of MSCs on improving islet function and ameliorating insulin resistance. More importantly, clinical trials have further uncovered the therapeutic potential of MSCs for T2DM. In this review, we outline current knowledge regarding the plasticity and underlying mechanisms of MSC-mediated immune modulation, focusing on the paracrine effects. We also summarize the applications of MSC-based therapies for T2DM in both preclinical studies and clinical trials, with particular emphasis on the modulation of immune system.
Collapse
Affiliation(s)
- Ji Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.,Department of Oral Implantology, School of Stomatology, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Cheng-Hu Hu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, People's Republic of China
| |
Collapse
|
|
36
|
Hamdan H, Hashmi SK, Lazarus H, Gale RP, Qu W, El Fakih R. Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome? Blood Rev 2021; 46:100742. [PMID: 32854985 PMCID: PMC7425550 DOI: 10.1016/j.blre.2020.100742] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/02/2020] [Accepted: 08/06/2020] [Indexed: 12/25/2022]
Abstract
Mesenchymal stromal cells (MSC) have immune regulatory and tissue regenerative properties. MSCs are being studied as a therapy option for many inflammatory and immune disorders and are approved to treat acute graft-versus-host disease (GvHD). The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic and associated coronavirus infectious disease-19 (COVID-19) has claimed many lives. Innovative therapies are needed. Preliminary data using MSCs in the setting of acute respiratory distress syndrome (ARDS) in COVID-19 are emerging. We review mechanisms of action of MSCs in inflammatory and immune conditions and discuss a potential role in persons with COVID-19.
Collapse
Affiliation(s)
- Hamdan Hamdan
- Department of Physiology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia,Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Shahrukh K. Hashmi
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA,Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hillard Lazarus
- Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, USA
| | | | - Wenchun Qu
- Department of Pain Medicine, Mayo Clinic, Jacksonville, FL, USA,Center of Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Riad El Fakih
- Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia,Corresponding author at: Oncology Centre, KFSHRC, Section of Adult Hematology/HSCT, PO Box 3354, Riyadh 11471, Saudi Arabia
| |
Collapse
|
|
37
|
Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties. Biomedicines 2021; 9:biomedicines9020209. [PMID: 33670708 PMCID: PMC7922639 DOI: 10.3390/biomedicines9020209] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 02/08/2023] Open
Abstract
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.
Collapse
|
|
38
|
Gan QF, Foo CN, Leong PP, Cheong SK. Incorporating regenerative medicine into rehabilitation programmes: a potential treatment for ankle sprain. INTERNATIONAL JOURNAL OF THERAPY AND REHABILITATION 2021. [DOI: 10.12968/ijtr.2019.0119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Ankle sprain has a great effect on morbidity and complications of chronic diseases. Experts have come to a consensus where ankle sprain can be managed by rest, ice, compression and elevation, non-steroidal anti-inflammatory drugs, immobilisation, functional support such as the use of an ankle brace, exercise, surgery and other therapies that include physiotherapy modalities and acupuncture. However, the time required for healing is still relatively long in addition to post-operative complications. Because of the challenges and setbacks faced by interventions to manage ankle sprains and in view of the recent trend and development in the field of regenerative medicine, this article discusses future treatments focusing on a personalised and holistic approach for ankle sprain management. This narrative review provides a novel idea for incorporating regenerative medicine into conventional therapy as an intervention for ankle sprain based on theoretical concepts and available evidence on regenerative medicine involving ligament injuries.
Collapse
Affiliation(s)
- Quan Fu Gan
- Pre-clinical Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Chai Nien Foo
- Population Medicine Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Pooi Pooi Leong
- Pre-clinical Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Soon Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| |
Collapse
|
|
39
|
Zhang Y, Lian M, Zhao X, Cao P, Xiao J, Shen S, Tang W, Zhang J, Hao J, Feng X. RICK regulates the odontogenic differentiation of dental pulp stem cells through activation of TNF-α via the ERK and not through NF-κB signaling pathway. Cell Biol Int 2021; 45:569-579. [PMID: 33169892 DOI: 10.1002/cbin.11498] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 10/17/2020] [Accepted: 10/31/2020] [Indexed: 12/27/2022]
Abstract
Dental pulp stem cells (DPSCs) are capable of both self-renewal and multilineage differentiation, which play a positive role in dentinogenesis. Studies have shown that tumor necrosis factor-α (TNF-α) is involved in the differentiation of DPSCs under pro-inflammatory stimuli, but the mechanism of action of TNF-α is unknown. Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) is a biomarker of an early inflammatory response that plays a key role in modulating cell differentiation, but the role of RICK in DPSCs is still unclear. In this study, we identified that RICK regulates TNF-α-mediated odontogenic differentiation of DPSCs via the ERK signaling pathway. The expression of the biomarkers of odontogenic differentiation dental matrix protein-1 (DMP-1), dentin sialophosphoprotein (DSPP), biomarkers of odontogenic differentiation, increased in low concentration (1-10 ng/ml) of TNF-α and decreased in high concentration (50-100 ng/ml). Odontogenic differentiation increased over time in the odontogenic differentiation medium. In the presence of 10 ng/L TNF-α, the expression of RICK increased gradually over time, along with odontogenic differentiation. Genetic silencing of RICK expression reduced the expression of odontogenic markers DMP-1 and DSPP. The ERK, but not the NF-κB signaling pathway, was activated during the odontogenic differentiation of DPSCs. ERK signaling modulators decreased when RICK expression was inhibited. PD98059, an ERK inhibitor, blocked the odontogenic differentiation of DPSCs induced by TNF-α. These results provide a further theoretical and experimental basis for the potential use of RICK in targeted therapy for dentin regeneration.
Collapse
Affiliation(s)
- Ye Zhang
- Jiangsu Vocational College of Medicine, Yancheng, China.,Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Min Lian
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xin Zhao
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Peipei Cao
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jingwen Xiao
- Department of Stomatology, Haimen People's Hospital, Nantong, China
| | - Shuling Shen
- Department of Stomatology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Wanxian Tang
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiaxuan Zhang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Jie Hao
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
40
|
Hosseini-Asl SK, Mehrabani D, Karimi-Busheri F. Therapeutic Effect of Mesenchymal Stem Cells in Ulcerative Colitis: A Review on Achievements and Challenges. J Clin Med 2020; 9:E3922. [PMID: 33287220 PMCID: PMC7761671 DOI: 10.3390/jcm9123922] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
The worldwide epidemiology of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), still shows an increasing trend in Asia and Iran. Despite an improvement in the treatment landscape focused on symptomatic control, long-term colectomies have not decreased over the last 10-year period. Thus, novel therapies are urgently needed in clinics to supplement the existing treatments. Mesenchymal stem cells (MSCs) are multipotent adult stem cells with immunosuppressive effects, targeting IBD as a new treatment strategy. They have recently received global attention for their use in cell transplantation due to their easy expansion and wide range of activities to be engrafted, and because they are home to the mucosa of the intestine. Moreover, MSCs are able to differentiate into epithelial and other cells that can directly promote repair in the mucosal damages in UC. It seems that there is a need to deepen our understanding to target MSCs as a promising treatment option for UC patients who are refractory to conventional therapies. Here, we overviewed the therapeutic effects of MSCs in UC and discussed the achievements and challenges in the cell transplantation of UC.
Collapse
Affiliation(s)
- Seyed-Kazem Hosseini-Asl
- Department of Internal Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars 71348-14336, Iran
| | - Davood Mehrabani
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Fars 71348-14336, Iran
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Fars 71987-74731, Iran
- Comparative and Experimental Medicine Center, Shiraz University of Medical Sciences, Shiraz, Fars 71348-14336, Iran
| | - Feridoun Karimi-Busheri
- Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, AB T6G 1Z2, Canada
| |
Collapse
|
|
41
|
Shin TH, Ahn JS, Oh SJ, Shin YY, Yang JW, Kang MJ, Kim JM, Lee BJ, Seo Y, Kim HS. TNF-α Priming Elicits Robust Immunomodulatory Potential of Human Tonsil-Derived Mesenchymal Stem Cells to Alleviate Murine Colitis. Biomedicines 2020; 8:biomedicines8120561. [PMID: 33276479 PMCID: PMC7760130 DOI: 10.3390/biomedicines8120561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).
Collapse
Affiliation(s)
- Tae-Hoon Shin
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Ji-Su Ahn
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Su-Jeong Oh
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Ye Young Shin
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Ji Won Yang
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Min-Jung Kang
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Ji Min Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan 49241, Korea; (J.M.K); (B.-J.L.)
| | - Byung-Joo Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan 49241, Korea; (J.M.K); (B.-J.L.)
| | - Yoojin Seo
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
- Correspondence: (Y.S.); (H.-S.K.); Tel.: +82-51-510-8231 (Y.S.); +82-10-5283-0721 (H.-S.K.)
| | - Hyung-Sik Kim
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.); (M.-J.K.)
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea
- Correspondence: (Y.S.); (H.-S.K.); Tel.: +82-51-510-8231 (Y.S.); +82-10-5283-0721 (H.-S.K.)
| |
Collapse
|
|
42
|
Seo Y, Park SY, Kim HS, Nam JS. The Hippo-YAP Signaling as Guardian in the Pool of Intestinal Stem Cells. Biomedicines 2020; 8:biomedicines8120560. [PMID: 33271948 PMCID: PMC7760694 DOI: 10.3390/biomedicines8120560] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite endogenous insults such as mechanical stress and danger signals derived from the microbiome, the intestine can maintain its homeostatic condition through continuous self-renewal of the crypt–villus axis. This extraordinarily rapid turnover of intestinal epithelium, known to be 3 to 5 days, can be achieved by dynamic regulation of intestinal stem cells (ISCs). The crypt base-located leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) ISCs maintain intestinal integrity in the steady state. Under severe damage leading to the loss of conventional ISCs, quiescent stem cells and even differentiated cells can be reactivated into stem-cell-like cells with multi-potency and contribute to the reconstruction of the intestinal epithelium. This process requires fine-tuning of the various signaling pathways, including the Hippo–YAP system. In this review, we summarize recent advances in understanding the correlation between Hippo–YAP signaling and intestinal homeostasis, repair, and tumorigenesis, focusing specifically on ISC regulation.
Collapse
Affiliation(s)
- Yoojin Seo
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea;
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - So-Yeon Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea;
| | - Hyung-Sik Kim
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea;
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
- Correspondence: (H.-S.K.); (J.-S.N.); Tel.: +82-51-510-8231 (H.-S.K.); +82-62-715-2893 (J.-S.N.)
| | - Jeong-Seok Nam
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea;
- Correspondence: (H.-S.K.); (J.-S.N.); Tel.: +82-51-510-8231 (H.-S.K.); +82-62-715-2893 (J.-S.N.)
| |
Collapse
|
|
43
|
Li Y, Ma K, Zhang L, Xu H, Zhang N. Human Umbilical Cord Blood Derived-Mesenchymal Stem Cells Alleviate Dextran Sulfate Sodium-Induced Colitis by Increasing Regulatory T Cells in Mice. Front Cell Dev Biol 2020; 8:604021. [PMID: 33330503 PMCID: PMC7732515 DOI: 10.3389/fcell.2020.604021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD), which main clinical manifestations include abdominal pain and diarrhea occurring repeatedly, is a kind of autoimmune disease. It has been reported in preceding studies that mesenchymal stem cells (MSCs) can reduce inflammation by regulating the function of immune cells. But studies about the interaction between MSCs and adaptive immune cells, especially in IBD models, are insufficient. Therefore, the objective of this research was to estimate the therapeutic effects of MSCs from human umbilical cord blood (hUCB-MSCs) in an IBD model of rodent and to clarify the therapeutic mechanisms of hUCB-MSCs. Dextran sulfate sodium (DSS) was used to induce colitis in rodent. Mice with colitis were treated with intraperitoneal infusions of hUCB-MSCs and evaluated for mortality and diverse disease symptoms containing weight reduction, diarrhea, and bloody stools. The levels of histopathologic severity and generation of regulatory T cells (Treg) were also determined. Treatment with hUCB-MSCs ameliorated the clinical and histopathologic severity of acute and chronic colitis in mice. Furthermore, T cell infiltration into the inflamed colon was significantly decreased (p = 0.0175), and Foxp3+ cells were substantially higher in the hUCB-MSC group than that of the DSS group. Our results suggest that hUCB-MSCs are able to alleviate inflammation via adding Foxp3+ Tregs in an IBD model of mouse. As a result, these findings suggest the opportunity of hUCB-MSC being applied to patients with IBD.
Collapse
Affiliation(s)
- Ying Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Ke Ma
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Luping Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Nan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
44
|
Yang JW, Seo Y, Shin TH, Ahn JS, Oh SJ, Shin YY, Kang MJ, Lee BC, Lee S, Kang KS, Hur J, Kim YS, Kim TY, Kim HS. Extracellular Vesicles from SOD3-Transduced Stem Cells Exhibit Improved Immunomodulatory Abilities in the Murine Dermatitis Model. Antioxidants (Basel) 2020; 9:E1165. [PMID: 33238520 PMCID: PMC7700433 DOI: 10.3390/antiox9111165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/10/2020] [Accepted: 11/19/2020] [Indexed: 12/28/2022] Open
Abstract
The immunoregulatory abilities of mesenchymal stem cells (MSCs) have been investigated in various autoimmune and allergic diseases. However, the therapeutic benefits observed in preclinical settings have not been reproducible in clinical trials. This discrepancy is due to insufficient efficacy of MSCs in harsh microenvironments, as well as batch-dependent variability in potency. Therefore, to achieve more beneficial and uniform outcomes, novel strategies are required to potentiate the therapeutic effect of MSCs. One of simple strategies to augment cellular function is genetic manipulation. Several studies showed that transduction of antioxidant enzyme into cells can increase anti-inflammatory effects. Therefore, we evaluated the immunoregulatory abilities of MSCs introduced with extracellular superoxide dismutase 3 (SOD3) in the present study. SOD3-overexpressed MSCs (SOD3-MSCs) reduced the symptoms of murine model of atopic dermatitis (AD)-like inflammation, as well as the differentiation and activation of various immune cells involved in AD progression. Interestingly, extracellular vesicles (EVs) isolated from SOD3-MSCs delivered SOD3 protein. EVs carrying SOD3 also exerted improved therapeutic efficacy, as observed in their parent cells. These results suggest that MSCs transduced with SOD3, an antioxidant enzyme, as well as EVs isolated from modified cells, might be developed as a promising cell-based therapeutics for inflammatory disorders.
Collapse
Affiliation(s)
- Ji Won Yang
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (J.W.Y.); (J.-S.A.); (S.-J.O.); (Y.Y.S.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Yoojin Seo
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Tae-Hoon Shin
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; (T.-H.S.); (B.-C.L.)
| | - Ji-Su Ahn
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (J.W.Y.); (J.-S.A.); (S.-J.O.); (Y.Y.S.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Su-Jeong Oh
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (J.W.Y.); (J.-S.A.); (S.-J.O.); (Y.Y.S.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Ye Young Shin
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (J.W.Y.); (J.-S.A.); (S.-J.O.); (Y.Y.S.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Min-Jung Kang
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| | - Byung-Chul Lee
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; (T.-H.S.); (B.-C.L.)
| | - Seunghee Lee
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul 08826, Korea; (S.L.); (K.-S.K.)
| | - Kyung-Sun Kang
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul 08826, Korea; (S.L.); (K.-S.K.)
- Adult Stem Cell Research Center and Research, Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Korea;
| | - Yeon-Soo Kim
- Graduate School of New Drug Discovery & Development, Chungnam National University, Daejeon 34134, Korea;
| | - Tae-Yoon Kim
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Hyung-Sik Kim
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (J.W.Y.); (J.-S.A.); (S.-J.O.); (Y.Y.S.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea; (Y.S.); (M.-J.K.)
| |
Collapse
|
|
45
|
Ryu JS, Jeong EJ, Kim JY, Park SJ, Ju WS, Kim CH, Kim JS, Choo YK. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. Int J Mol Sci 2020; 21:ijms21218366. [PMID: 33171878 PMCID: PMC7664655 DOI: 10.3390/ijms21218366] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.
Collapse
Affiliation(s)
- Jae-Sung Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Eun-Jeong Jeong
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Jong-Yeup Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Soon Ju Park
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Won Seok Ju
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Chang-Hyun Kim
- College of Medicine, Dongguk University, Goyang 10326, Korea;
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
| | - Young-Kug Choo
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
- Correspondence:
| |
Collapse
|
|
46
|
Tian J, Kou X, Wang R, Jing H, Chen C, Tang J, Mao X, Zhao B, Wei X, Shi S. Autophagy controls mesenchymal stem cell therapy in psychological stress colitis mice. Autophagy 2020; 17:2586-2603. [PMID: 32910719 DOI: 10.1080/15548627.2020.1821547] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cell transplantation (MSCT) has been applied to treat a variety of autoimmune and inflammatory diseases. Psychosocial stress can aggravate disease progression in chronic inflammatory patients. Whether psychological stress affects MSCT is largely unknown. In this study we show that psychological stress attenuates therapeutic effects of MSCT in a DSS-induced colitis mouse model by elevating the levels of exosomal Mir7k/mmu-let-7 k (microRNA 7 k) in circulation. Mechanistically, Mir7k inhibits STAT3 pathway in donor MSCs, leading to upregulated expression of BECN1 (beclin 1, autophagy related) and, thus, activation of macroautophagy/autophagy. Inhibition of autophagy by blocking Mir7k or activating STAT3 signaling can restore MSCT-mediated therapy in psychologically stressed colitis mice. Our study identifies a previously unknown role of autophagy in regulating MSCT therapy via exosomal miRNA Mir7k.Abbreviations: BafA1: bafilomycin A1; BECN1: beclin 1, autophagy related; DAI: disease activity index; DAPI: 4',6-diamidino-2-phenylindole; DSS: dextran sulfate sodium; GFP: green fluorescent protein; HAI: histological activity index; IFNG/IFN-γ: interferon gamma; IL10: interleukin 10; IL1RN/IL-1Rra: interleukin 1 receptor antagonist; KD: knockdown; miRNA: microRNA; MSCs: mesenchymal stem cells; MSCT: mesenchymal stem cell transplantation; NTA: nanoparticle tracking analysis; PGE2: prostaglandin E2; SD: standard deviation; siRNA: small-interfering RNA; STAT3: signal transducer and activator of transcription 3; TEM: transmission electron microscopy; TGFB1/TGF-β1: transforming growth factor, beta 1; Th17 cell: T helper cell 17; TNF/TNF-α: tumor necrosis factor; TNFAIP6/TSG6: tumor necrosis factor alpha induced protein 6; Tregs: regulatory T cells.
Collapse
Affiliation(s)
- Jun Tian
- Guanghua School of Stomatology, Affiliated Stomatological Hospital and Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Xiaoxing Kou
- Guanghua School of Stomatology, Affiliated Stomatological Hospital and Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Runci Wang
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Huan Jing
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Jianxia Tang
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Xueli Mao
- Guanghua School of Stomatology, Affiliated Stomatological Hospital and Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Bingjiao Zhao
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Xi Wei
- Guanghua School of Stomatology, Affiliated Stomatological Hospital and Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Songtao Shi
- Guanghua School of Stomatology, Affiliated Stomatological Hospital and Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| |
Collapse
|
|
47
|
Lee BC, Kang KS. Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application. Stem Cell Res Ther 2020; 11:397. [PMID: 32928306 PMCID: PMC7491075 DOI: 10.1186/s13287-020-01920-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/17/2020] [Accepted: 09/01/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have recently been considered a promising alternative treatment for diverse immune disorders due to their unique biomedical potentials including the immunomodulatory property and ability to promote tissue regeneration. However, despite many years of pre-clinical studies in the research field, results from clinical trials using these cells have been diverse and conflicting. This discrepancy is caused by several factors such as poor engraftment, low survival rate, and donor-dependent variation of the cells. Enhancement of consistency and efficacy of MSCs remains a challenge to overcome the current obstacles to MSC-based therapy and subsequently achieve an improved therapeutic outcome. In this review, we investigated function enhancement strategies by categorizing as preconditioning, genetic manipulation, usage of supportive materials, and co-administration with currently used drugs. Preconditioning prior to MSC application makes up a large proportion of improvement strategies and preconditioning reagents include bioactive substances (cytokines, growth factors, and innate immune receptor agonists), hypoxia, and modification in culture method. With the piled results from previous studies using each method, disease- or patient-specific therapy has become more important than ever. On the other hand, genetic manipulation targeting therapeutic-associated factors or co-administration of biocompatible materials has also arisen as other therapeutic strategies. Thus, we summarized several specialized tactics by analyzing up-to-date results in the field and proposed some promising enhancement methods to improve the clinical outcomes for MSC therapy.
Collapse
Affiliation(s)
- Byung-Chul Lee
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
| |
Collapse
|
|
48
|
Kang JY, Oh MK, Joo H, Park HS, Chae DH, Kim J, Lee HR, Oh IH, Yu KR. Xeno-Free Condition Enhances Therapeutic Functions of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis by Upregulated Indoleamine 2,3-Dioxygenase Activity. J Clin Med 2020; 9:jcm9092913. [PMID: 32927587 PMCID: PMC7565923 DOI: 10.3390/jcm9092913] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022] Open
Abstract
The therapeutic applications of mesenchymal stem cells (MSCs) have been actively explored due to their broad anti-inflammatory and immunomodulatory properties. However, the use of xenogeneic components, including fetal bovine serum (FBS), in the expansion media might pose a risk of xenoimmunization and zoonotic transmission to post-transplanted patients. Here, we extensively compared the physiological functions of human Wharton’s jelly-derived MSCs (WJ-MSCs) in a xeno-free medium (XF-MSCs) and a medium containing 10% FBS (10%-MSCs). Both groups showed similar proliferation potential; however, the 10%-MSCs showed prolonged expression of CD146, with higher colony-forming unit-fibroblast (CFU-F) ability than the XF-MSCs. The XF-MSCs showed enhanced adipogenic differentiation potential and sufficient hematopoietic stem cell (HSC) niche activity, with elevated niche-related markers including CXCL12. Furthermore, we demonstrated that the XF-MSCs had a significantly higher suppressive effect on human peripheral blood-derived T cell proliferation, Th1 and Th17 differentiation, as well as naïve macrophage polarization toward an M1 phenotype. Among the anti-inflammatory molecules, the production of indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase 2 (NOS2) was profoundly increased, whereas cyclooxygenase-2 (COX-2) was decreased in the XF-MSCs. Finally, the XF-MSCs had an enhanced therapeutic effect against mouse experimental colitis. These findings indicate that xeno-free culture conditions improved the immunomodulatory properties of WJ-MSCs and ex vivo-expanded XF-MSCs might be an effective strategy for preventing the progression of colitis.
Collapse
Affiliation(s)
- Ji Yeon Kang
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
| | - Mi-Kyung Oh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
| | - Hansol Joo
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
| | - Hyun Sung Park
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
| | - Dong-Hoon Chae
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
| | - Jieun Kim
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungcheongbuk-do 28116, Korea
| | - Hae-Ri Lee
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul 08826, Korea;
| | - Il-Hoan Oh
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul 08826, Korea;
- Correspondence: (I.-H.O.); (K.-R.Y.)
| | - Kyung-Rok Yu
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 08826, Korea; (J.Y.K.); (M.-K.O.); (H.J.); (H.S.P.); (D.-H.C.); (J.K.)
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
- Correspondence: (I.-H.O.); (K.-R.Y.)
| |
Collapse
|
|
49
|
Zhang X, Wang S, Ding X, Guo J, Tian Z. Potential methods for improving the efficacy of mesenchymal stem cells in the treatment of inflammatory bowel diseases. Scand J Immunol 2020; 92:e12897. [PMID: 32443180 DOI: 10.1111/sji.12897] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBD) are a group of chronic recurrent gastrointestinal inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) and IBD unclassified. The pathogenesis may be related to the mucosal immune dysfunction in genetically susceptible hosts affected by environmental factors. Current therapeutic agents mainly include aminosalicylates, corticosteroids, immunosuppressive drugs and novel biological agents. The purpose of treatment is to suppress inflammation and prevent irreversible structural damage. However, long-term application of these drugs may lead to multiple adverse effects and is not always effective. Mesenchymal stem cells (MSCs) are multipotent progenitors with low immunogenicity, which can be obtained and expanded easily. They play an important role in regulating immune responses and repairing damaged tissues in vivo. Therefore, MSCs are considered to be a promising option for the treatment of IBD. Nonetheless, there are many factors that can reduce the efficacy of MSCs, such as gradual deterioration of functional stem cells with age, low recruitment and persistence in vivo and different routes of administration. In recent years, researchers have been able to improve the efficacy of MSCs by pretreatment, genetic modification or co-application with other substances, as well as using different tissue-derived cells, administration methods or doses. This article reviews these methods to provide references for more effective application of MSCs in the treatment of IBD in the future.
Collapse
Affiliation(s)
- Xiaofei Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shaojun Wang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xueli Ding
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zibin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
50
|
Park HH, Lee S, Yu Y, Yoo SM, Baek SY, Jung N, Seo KW, Kang KS. TGF-β secreted by human umbilical cord blood-derived mesenchymal stem cells ameliorates atopic dermatitis by inhibiting secretion of TNF-α and IgE. Stem Cells 2020; 38:904-916. [PMID: 32277785 DOI: 10.1002/stem.3183] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/03/2020] [Accepted: 03/17/2020] [Indexed: 12/20/2022]
Abstract
Human mesenchymal stem cells (MSCs) are promising therapeutics for autoimmune diseases due to their immunomodulatory effects. In particular, human umbilical cord blood-derived MSCs (hUCB-MSCs) have a prominent therapeutic effect on atopic dermatitis (AD). However, the underlying mechanism is unclear. This study investigated the role of transforming growth factor-beta (TGF-β) in the therapeutic effect of hUCB-MSCs on AD. Small interfering RNA (siRNA)-mediated depletion of TGF-β disrupted the therapeutic effect of hUCB-MSCs in a mouse model of AD by attenuating the beneficial changes in histopathology, mast cell infiltration, tumor necrosis factor-alpha (TNF-α) expression, and the serum IgE level. To confirm that hUCB-MSCs regulate secretion of TNF-α, we investigated whether they inhibit TNF-α secretion by activated LAD2 cells. Coculture with hUCB-MSCs significantly inhibited secretion of TNF-α by LAD2 cells. However, this effect was abolished by siRNA-mediated depletion of TGF-β in hUCB-MSCs. TNF-α expression in activated LAD2 cells was regulated by the extracellular signal-related kinase signaling pathway and was suppressed by TGF-β secreted from hUCB-MSCs. In addition, TGF-β secreted by hUCB-MSCs inhibited maturation of B cells. Taken together, our findings suggest that TGF-β plays a key role in the therapeutic effect of hUCB-MSCs on AD by regulating TNF-α in mast cells and maturation of B cells.
Collapse
Affiliation(s)
- Hwan Hee Park
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Yeonsil Yu
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Sae Mi Yoo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Song Yi Baek
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Namhee Jung
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kwang-Won Seo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kyung-Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| |
Collapse
|