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Lee E, Lim GH, An JH, Ryu MO, Seo KW, Youn HY. Enhanced immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells in 3D culture. Front Vet Sci 2025; 12:1500267. [PMID: 40206260 PMCID: PMC11979191 DOI: 10.3389/fvets.2025.1500267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 03/03/2025] [Indexed: 04/11/2025] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) have been introduced as a treatment for dogs owing to their immunomodulatory effects. In humans, 3D-cultured MSCs have recently been applied in treating various conditions, including myocardial infarction, liver disease, and kidney disease. This study aimed to evaluate whether the immunomodulatory effects of canine adipose tissue-derived MSCs (cAT-MSCs) are enhanced when cultured in a 3D environment compared to conventional 2D culture. Methods cAT-MSC spheroids were generated using ultra-low-adhesion plates. The structural and hypoxic characteristics of these spheroids were assessed via confocal imaging. The expression levels of the stemness markers SOX2 and OCT4 were examined through western blotting. Additionally, the expression of inflammatory factors within the cAT-MSC spheroids was analyzed using RT-PCR and ELISA. The immunomodulatory effects were further evaluated in canine macrophages (DH82) treated with conditioned media (CM) from cAT-MSC spheroids, using RT-PCR and flow cytometry. Results 3D culture induced hypoxic conditions within the cAT-MSC spheroids and significantly increased the expression of SOX2 and OCT4 (p < 0.05). Moreover, the expression of inflammation-associated factors, including TGF-β1, TSG-6, COX-2, PGE2, and IL-10, was upregulated in the 3D culture (p < 0.05). Treatment of DH82 cells with CM from the cAT-MSC spheroids led to a significant reduction in the expression of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6 (p < 0.01). Additionally, M1 polarization was diminished in DH82 cells exposed to the CM from the cAT-MSC spheroids (p < 0.0001). And M2 polarization was increased in DH82 cells exposed to the CM from the cAT-MSC spheroids (p < 0.0001). Conclusion This study confirms that the immunomodulatory effects of MSCs are enhanced in 3D culture. Therefore, 3D cultured MSCs may offer a more effective therapeutic approach than conventional 2D-cultured MSCs for treating canine inflammatory diseases.
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Affiliation(s)
- Eunbi Lee
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ga-Hyun Lim
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
- VIP Animal Medical Center, Seoul, Republic of Korea
| | - Ju-Hyun An
- Department of Veterinary Emergency and Critical Care Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, Chuncheon-si, Republic of Korea
| | - Min-Ok Ryu
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Kyoung-Won Seo
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hwa-Young Youn
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
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Hurtado-Lorenzo A, Swantek JL. The landscape of new therapeutic opportunities for IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:1-83. [PMID: 39521596 DOI: 10.1016/bs.apha.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.
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Affiliation(s)
- Andrés Hurtado-Lorenzo
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States.
| | - Jennifer L Swantek
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States
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Kurawaki S, Nakashima A, Ishiuchi N, Kanai R, Maeda S, Sasaki K, Masaki T. Mesenchymal stem cells pretreated with interferon-gamma attenuate renal fibrosis by enhancing regulatory T cell induction. Sci Rep 2024; 14:10251. [PMID: 38704512 PMCID: PMC11069572 DOI: 10.1038/s41598-024-60928-4] [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: 05/22/2023] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
Mesenchymal stem cells (MSCs) exert their anti-inflammatory and anti-fibrotic effects by secreting various humoral factors. Interferon-gamma (IFN-γ) can enhance these effects of MSCs, and enhancement of regulatory T (Treg) cell induction is thought to be an underlying mechanism. However, the extent to which Treg cell induction by MSCs pretreated with IFN-γ (IFN-γ MSCs) ameliorates renal fibrosis remains unknown. In this study, we investigated the effects of Treg cell induction by IFN-γ MSCs on renal inflammation and fibrosis using an siRNA knockdown system. Administration of IFN-γ MSCs induced Treg cells and inhibited infiltration of inflammatory cells in ischemia reperfusion injury (IRI) rats more drastically than control MSCs without IFN-γ pretreatment. In addition, administration of IFN-γ MSCs more significantly attenuated renal fibrosis compared with control MSCs. Indoleamine 2,3-dioxygenase (IDO) expression levels in conditioned medium from MSCs were enhanced by IFN-γ pretreatment. Moreover, IDO1 knockdown in IFN-γ MSCs reduced their anti-inflammatory and anti-fibrotic effects in IRI rats by reducing Treg cell induction. Our findings suggest that the increase of Treg cells induced by enhanced secretion of IDO by IFN-γ MSCs played a pivotal role in their anti-fibrotic effects. Administration of IFN-γ MSCs may potentially be a useful therapy to prevent renal fibrosis progression.
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Affiliation(s)
- So Kurawaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Ryo Kanai
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Satoshi Maeda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
- TWOCELLS Company, Limited, 16-35 Hijiyama-honmachi, Minami-ku, Hiroshima, 732-0816, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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Dong Y, Johnson BA, Ruan L, Zeineldin M, Bi T, Liu AZ, Raychaudhuri S, Chiu I, Zhu J, Smith B, Zhao N, Searson P, Watanabe S, Donowitz M, Larman TC, Li R. Disruption of epithelium integrity by inflammation-associated fibroblasts through prostaglandin signaling. SCIENCE ADVANCES 2024; 10:eadj7666. [PMID: 38569041 PMCID: PMC10990275 DOI: 10.1126/sciadv.adj7666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 02/27/2024] [Indexed: 04/05/2024]
Abstract
Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.
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Affiliation(s)
- Yi Dong
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Blake A. Johnson
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Linhao Ruan
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Maged Zeineldin
- Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Tianhao Bi
- Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Albert Z. Liu
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Sumana Raychaudhuri
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Ian Chiu
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Jin Zhu
- Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Barbara Smith
- Microscope Facility, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Nan Zhao
- Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Peter Searson
- Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Shigeki Watanabe
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
- Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Tatianna C. Larman
- Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Rong Li
- Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
- Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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Teshima T. Heterogeneity of mesenchymal stem cells as a limiting factor in their clinical application to inflammatory bowel disease in dogs and cats. Vet J 2024; 304:106090. [PMID: 38417670 DOI: 10.1016/j.tvjl.2024.106090] [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: 10/28/2023] [Revised: 02/22/2024] [Accepted: 02/25/2024] [Indexed: 03/01/2024]
Abstract
Inflammatory bowel disease (IBD) is a major subtype of chronic enteropathies in dogs and cats. Conventional drugs such as immunomodulatory medicines as glucocorticoids and/or other anti-inflammatory are mainly applied for treatment. However, these drugs are not always effective to maintain remission from IBD and are limited by unacceptable side effects. Hence, more effective and safe therapeutic options need to be developed. Mesenchymal stem cells (MSCs) are multipotent stem cells with a self-renewal capacity, and have immunomodulatory, anti-inflammatory, anti-fibrotic, and tissue repair properties. Therefore, the application of MSCs as an alternative therapy for IBD has great potential in veterinary medicine. The efficacy of adipose tissue-derived MSC (ADSC) therapy for IBD in dogs and cats has been reported, including numerous studies in animal models. However, treatment outcomes in clinical trials of human IBD patients have not been consistent with preclinical studies. MSC-based therapy for various diseases has received widespread attention, but various problems in such therapy remain, among which no consensus has been reached on the preparation and treatment procedures for MSCs, and cellular heterogeneity of MSCs may be an issue. This review describes the current status of ADSC therapy for canine and feline IBD and summarizes the cellular heterogeneity of canine ADSCs, to highlight the necessity for further reduction or elimination of MSCs heterogeneity and standardization of MSC-based therapies.
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Affiliation(s)
- Takahiro Teshima
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Japan; Research Center for Animal Life Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180-8602, Japan.
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Sun T, Zhou C, Lu F, Dong Z, Gao J, Li B. Adipose-derived stem cells in immune-related skin disease: a review of current research and underlying mechanisms. Stem Cell Res Ther 2024; 15:37. [PMID: 38331803 PMCID: PMC10854049 DOI: 10.1186/s13287-023-03561-8] [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: 11/28/2022] [Accepted: 11/06/2023] [Indexed: 02/10/2024] Open
Abstract
Adipose-derived stem cells (ASCs) are a critical adult stem cell subpopulation and are widely utilized in the fields of regenerative medicine and stem cell research due to their abundance, ease of harvest, and low immunogenicity. ASCs, which are homologous with skin by nature, can treat immune-related skin diseases by promoting skin regeneration and conferring immunosuppressive effects, with the latter being the most important therapeutic mechanism. ASCs regulate the immune response by direct cell-cell communication with immune cells, such as T cells, macrophages, and B cells. In addition to cell-cell interactions, ASCs modulate the immune response indirectly by secreting cytokines, interleukins, growth factors, and extracellular vesicles. The immunomodulatory effects of ASCs have been exploited to treat many immune-related skin diseases with good therapeutic outcomes. This article reviews the mechanisms underlying the immunomodulatory effects of ASCs, as well as progress in research on immune-related skin diseases.
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Affiliation(s)
- Tianyi Sun
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Cheng Zhou
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Feng Lu
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Ziqing Dong
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Jianhua Gao
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Bin Li
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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Smyth M, Lunken G, Jacobson K. Insights Into Inflammatory Bowel Disease and Effects of Dietary Fatty Acid Intake With a Focus on Polyunsaturated Fatty Acids Using Preclinical Models. J Can Assoc Gastroenterol 2024; 7:104-114. [PMID: 38314173 PMCID: PMC10837003 DOI: 10.1093/jcag/gwad058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2024] Open
Abstract
While the aetiology of inflammatory bowel disease (IBD) has been linked to genetic susceptibility coupled with environmental factors, the underlying molecular mechanisms remain unclear. Among the environmental factors, diet and the gut microbiota have been implicated as drivers of immune dysregulation in IBD. Indeed, epidemiologic studies have highlighted that the increase in incidence of IBD parallels the increase in dietary intake of omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and the change in balance of intake of n-6 to n-3 fatty acids. Experimental evidence suggests that the increase in n-6 PUFA intake increases cell membrane arachidonic acid, which is accompanied by the production of pro-inflammatory mediators as well as increased oxidative stress; together, this contributes to the development of chronic inflammation. However, it is also increasingly clear that some of the n-6 PUFA-derived mediators exert beneficial effects depending on the settings and timing of ingestion. In contrast to n-6, when n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid are incorporated into the cell membrane and are metabolized into less pro-inflammatory eicosanoids, as well as strong specialized pro-resolving mediators, which play a role in inflammation cessation. With a focus on preclinical models, we explore the relationship between dietary lipid, the gut microbiome, and intestinal inflammation.
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Affiliation(s)
- Matthew Smyth
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, B.C., Vancouver, British Columbia, Canada, V6H 3V4
| | - Genelle Lunken
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, B.C., Vancouver, British Columbia, Canada, V6H 3V4
- British Columbia Children Hospital Research Institute,Vancouver, British Columbia, Canada, V5Z 4H4
| | - Kevan Jacobson
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, B.C., Vancouver, British Columbia, Canada, V6H 3V4
- British Columbia Children Hospital Research Institute,Vancouver, British Columbia, Canada, V5Z 4H4
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada, V6T 2A1
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Jeon S, Kim I, Na YR, Yong Hong K, Chang H, Kim SH, Jeong YJ, Chung JH, Kim SW. Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation. Tissue Eng Regen Med 2023; 20:905-919. [PMID: 37531072 PMCID: PMC10519904 DOI: 10.1007/s13770-023-00552-x] [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: 03/21/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Adipose-derived stem cells (ADSCs) exert immunomodulatory effects in the treatment of transplant rejection. This study aimed to evaluate the effects of ADSCs on the skin graft survival in a human-to-rat xenograft transplantation model and to compare single and multiple injections of ADSCs. METHODS Full-thickness human skin xenografts were transplanted into the backs of Sprague-Dawley rats. The rats were injected subcutaneously on postoperative days 0, 3, and 5. The injections were as follows: triple injections of phosphate-buffered saline (PBS group), a single injection of ADSCs and double injections of PBS (ADSC × 1 group), and triple injections of ADSCs (ADSC × 3 group). The immunomodulatory effects of ADSCs on human skin xenografts were assessed. RESULTS Triple injections of ADSCs considerably delayed cell-mediated xenograft rejection compared with the PBS and ADSC × 1 groups. The vascularization and collagen type 1-3 ratios in the ADSC × 3 group were significantly higher than those in the other groups. In addition, intragraft infiltration of CD3-, CD4-, CD8-, and CD68-positive cells was reduced in the ADSC × 3 group. Furthermore, in the ADSC × 3 group, the expression levels of proinflammatory cytokine interferon-gamma (IFN-γ) were decreased and immunosuppressive prostaglandin E synthase (PGES) was increased in the xenograft and lymph node samples. CONCLUSION This study presented that triple injections of ADSCs appeared to be superior to a single injection in suppressing cell-mediated xenograft rejection. The immunomodulatory effects of ADSCs are associated with the downregulation of IFN-γ and upregulation of PGES in skin xenografts and lymph nodes.
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Affiliation(s)
- Sungmi Jeon
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Plastic and Reconstructive Surgery, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Iljin Kim
- Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University, Incheon, 22212, Republic of Korea
| | - Yi Rang Na
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University Medical College, Seoul, Republic of Korea
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Ki Yong Hong
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hak Chang
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Hwan Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yu Jin Jeong
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jee Hyeok Chung
- Division of Pediatric Plastic Surgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
| | - Sang Wha Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Dong Y, Johnson BA, Ruan L, Zeineldin M, Liu AZ, Raychaudhuri S, Chiu I, Zhu J, Smith B, Zhao N, Searson P, Watanabe S, Donowitz M, Larman TC, Li R. Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.28.560060. [PMID: 37808771 PMCID: PMC10557697 DOI: 10.1101/2023.09.28.560060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed an in vitro model whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFs in vivo. When co-cultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid swelling and barrier disruption due to swelling and rupture of individual epithelial cells. Epithelial cells co-cultured with IAFs also exhibit increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated through a paracrine pathway involving prostaglandin E2 (PGE2) and the PGE2 receptor EP4, leading to PKA-dependent activation of the CFTR chloride channel. Importantly, EP4-specific chemical inhibitors effectively prevented colonoid swelling and restored normal proliferation and genome stability of IAF-exposed epithelial cells. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a potential treatment to mitigate inflammation-associated epithelial injury.
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Affiliation(s)
- Yi Dong
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Blake A. Johnson
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Linhao Ruan
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Maged Zeineldin
- Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Albert Z. Liu
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Sumana Raychaudhuri
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Ian Chiu
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Jin Zhu
- Mechanobiology Institute and Department of Biological Sciences, National University of Singapore; Singapore
| | - Barbara Smith
- Microscope Facility, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Nan Zhao
- Institute for Nanobiotechnology, Johns Hopkins University; Baltimore, Maryland, 21218, U.S.A
| | - Peter Searson
- Institute for Nanobiotechnology, Johns Hopkins University; Baltimore, Maryland, 21218, U.S.A
- Department of Materials Science and Engineering, Johns Hopkins University; Baltimore, MD, 21218, U.S.A
| | - Shigeki Watanabe
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
- Department of Physiology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Tatianna C. Larman
- Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
| | - Rong Li
- Department of Cell Biology, Johns Hopkins School of Medicine; Baltimore, MD, 21205, U.S.A
- Mechanobiology Institute and Department of Biological Sciences, National University of Singapore; Singapore
- Department of Biological Sciences, National University of Singapore; Singapore
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Kim K, An JH, Park SM, Lim G, Seo KW, Youn HY. Amelioration of DSS-induced colitis in mice by TNF-α-stimulated mesenchymal stem cells derived from feline adipose tissue via COX-2/PGE 2 activation. J Vet Sci 2023; 24:e52. [PMID: 37532297 PMCID: PMC10404709 DOI: 10.4142/jvs.23106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/17/2023] [Accepted: 05/23/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been investigated as therapeutic agents for inflammatory bowel disease (IBD). Stimulation of MSCs with pro-inflammatory cytokines is an approach to enhance their immunomodulatory effects. However, further investigation is required to support their application in immune-mediated disorders and companion animals. OBJECTIVES This study aimed to assess the therapeutic effect of tumor necrosis factor (TNF)-α-stimulated feline adipose tissue-derived MSCs (fAT-MSCs) in a dextran sulfate sodium (DSS)-induced colitis mouse model. METHODS Colitis mice was made by drinking water with 3% DSS and fAT-MSCs were injected intraperitoneally. Colons were collected on day 10. The severity of the disease was evaluated and compared. Raw 264.7 cells were cultured with the conditioned medium to determine the mechanism, using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS TNF-α-stimulated fAT-MSCs more improved severity of DSS-induced colitis in disease activity, colon length, histologic score, and inflammatory cytokine. In sectionized colon tissues, the group comprising TNF-α-stimulated fAT-MSCs had higher proportion of CD11b+CD206+ macrophages than in the other groups. In vitro, TNF-α-stimulation increased cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) secretion from fAT-MSCs. The conditioned medium from TNF-α-stimulated fAT-MSCs enhanced the expression of interleukin-10 and arginase-1 in LPS-activated Raw 264.7 cells. CONCLUSIONS These results represent that TNF-α-stimulated fat-mscs ameliorate the inflamed colon more effectively. Furthermore, we demonstrated that the effectiveness was interlinked with the COX-2/PGE2 pathway.
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Affiliation(s)
- Kyeongbo Kim
- Laboratory of Veterinary Internal Medicine, Department of Clinical Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Ju-Hyun An
- Department of Veterinary Emergency and Critical Care Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Su-Min Park
- Laboratory of Veterinary Internal Medicine, Department of Clinical Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - GaHyun Lim
- Laboratory of Veterinary Internal Medicine, Department of Clinical Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Kyung-Won Seo
- Laboratory of Veterinary Internal Medicine, Department of Clinical Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Hwa-Young Youn
- Laboratory of Veterinary Internal Medicine, Department of Clinical Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
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11
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The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells. Biomedicines 2023; 11:biomedicines11020445. [PMID: 36830980 PMCID: PMC9952951 DOI: 10.3390/biomedicines11020445] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/27/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.
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12
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Hoang VT, Nguyen HP, Nguyen VN, Hoang DM, Nguyen TST, Nguyen Thanh L. “Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial”. Front Cell Dev Biol 2022; 10:956274. [PMID: 36247008 PMCID: PMC9554747 DOI: 10.3389/fcell.2022.956274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman’s syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Viet Nhan Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
| | - Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
- *Correspondence: Liem Nguyen Thanh,
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13
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Wu Y, Liu J, Hao H, Hu L, Zhang X, Luo L, Zeng J, Zhang W, Nam Wong I, Huang R. A new polysaccharide from Caulerpa chemnitzia induces molecular shifts of immunomodulation on macrophages RAW264.7. Food Chem X 2022; 14:100313. [PMID: 35539819 PMCID: PMC9079710 DOI: 10.1016/j.fochx.2022.100313] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 04/07/2022] [Accepted: 04/15/2022] [Indexed: 11/18/2022] Open
Abstract
Investigation on Caulerpa chemnitzia polysaccharides led to the finding of a new polysaccharide (CCP). The basic components of CCP were the total sugar (59.18% ± 0.57%), the uronic acids (36.75% ± 0.28%) and the sulfate (42.50% ± 0.42%), in total content. The physicochemical analysis revealed that CCP was a heteropolysaccharide with a molecular weight of 321.6 KDa, and composed of arabinose, fucose, glucose, mannose, galactose, xylose, fructose, ribose, glucuronic acid and galacturonic acid. The immunomodulatory assay showed that CCP played an important role in activating cell viability, the nitric oxide product and cytokines (IL-6 and TNF-α) secretion. Furthermore, the transcript-metabolic analysis displayed a total of 7692 differentially expressed genes (DEGs) and 95 differentially accumulated metabolites (DAMs), and revealed that CCP may play an immunomodulatory effect by activating NF-κB signaling pathway and arachidonic acid metabolism pathway. These findings will provide a basic understanding to further investigation of Caulerpa polysaccharides.
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Affiliation(s)
- Yulin Wu
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Jun Liu
- Laboratory of Pathogenic Biology, The Marine Biomedical Research Institute, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Huili Hao
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Lianmei Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Xiaoyong Zhang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Lianxiang Luo
- Laboratory of Pathogenic Biology, The Marine Biomedical Research Institute, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Jincheng Zeng
- Laboratory of Pathogenic Biology, The Marine Biomedical Research Institute, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Wei Zhang
- State Key Laboratory of Quality Research in Chinese Medicines and Macau Institute for Applied Research in Medicine and Health, Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau 999078, China
| | - Io Nam Wong
- State Key Laboratory of Quality Research in Chinese Medicines and Macau Institute for Applied Research in Medicine and Health, Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau 999078, China
| | - Riming Huang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
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14
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Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-Dependent Manner. Inflammation 2022; 45:2000-2015. [PMID: 35699823 DOI: 10.1007/s10753-022-01670-9] [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: 11/02/2021] [Revised: 01/26/2022] [Accepted: 04/08/2022] [Indexed: 11/05/2022]
Abstract
Mesenchymal stem cells (MSCs) have been demonstrated to attenuate acute lung injury (ALI). We also found that they can suppress the activation of alveolar macrophages (AMs), which can partly account for their therapeutic effects. MSCs do not inherently own immunosuppressive effects, when co-cultured with inflammatory immune cells, MSCs can be activated by inflammatory cytokines and meanwhile exert immunosuppressive effects. In order to further research, RNA sequencing (RNA-seq) of MSCs cultured before and after co-culturing with activated macrophages was performed. The data suggested a total of 5268 differentially expressed genes (DEGs) along the process. We used the data of 2754 upregulated DEGs to develop a signaling network of genes and the transcription factors targeting them in order to predict the altered functions of MSCs after exposure to inflammatory stimuli. This constructed network revealed some critical target genes and potential roles of MSCs under inflammatory conditions. According to the network, Ptgs2 was assumed to be an important gene participating in the immunosuppressive effects of MSCs. We also identified significant increases in the expression of COX2 protein and the secretion of PGE2 from MSCs. The use of the COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppression of macrophage activation by MSCs in vitro. In addition, a selective antagonist of PGE2 binding receptor (EP4 receptor), GW627368X, also reversed the inhibitory effects of MSCs on AMs and the protective effects in ALI mouse. In summary, the therapeutic effects of MSCs on ALI partly occur through suppressing AM activation via PGE2 binding to EP4 receptor.
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15
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Pro- and anti-inflammatory bioactive lipids imbalance contributes to the pathobiology of autoimmune diseases. Eur J Clin Nutr 2022:10.1038/s41430-022-01173-8. [PMID: 35701524 DOI: 10.1038/s41430-022-01173-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/22/2022] [Accepted: 05/26/2022] [Indexed: 12/27/2022]
Abstract
Autoimmune diseases are driven by TH17 cells that secrete pro-inflammatory cytokines, especially IL-17. Under normal physiological conditions, autoreactive T cells are suppressed by TGF-β and IL-10 secreted by microglia and dendritic cells. When this balance is upset due to injury, infection and other causes, leukocyte recruitment and macrophage activation occurs resulting in secretion of pro-inflammatory IL-6, TNF-α, IL-17 and PGE2, LTs (leukotrienes) accompanied by a deficiency of anti-inflammatory LXA4, resolvins, protecting, and maresins. PGE2 facilitates TH1 cell differentiation and promotes immune-mediated inflammation through TH17 expansion. There is evidence to suggest that autoimmune diseases can be suppressed by anti-inflammatory bioactive lipids LXA4, resolvins, protecting, and maresins. These results imply that systemic and/or local application of LXA4, resolvins, protecting, and maresins and administration of their precursors AA/EPA/DHA could form a potential therapeutic approach in the prevention and treatment of autoimmune diseases.
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16
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Robinson AM, Stavely R, Miller S, Eri R, Nurgali K. Mesenchymal stem cell treatment for enteric neuropathy in the Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 2022; 389:41-70. [PMID: 35536444 DOI: 10.1007/s00441-022-03633-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 04/26/2022] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic gut inflammation with periods of acute flares and remission. Beneficial effects of a single dose of mesenchymal stem cell (MSC)-based treatment have been demonstrated in acute models of colitis. No studies investigated therapeutic effects of MSCs for the attenuation of enteric neuropathy in a chronic model of colitis. The short and long-term effects of MSC treatment in modulating inflammation and damage to the enteric nervous system (ENS) were studied in the Winnie mouse model of spontaneous chronic colitis highly representative of human IBD. Winnie mice received a single dose of either 1 × 106 human bone marrow-derived MSCs or 100µL PBS by intracolonic enema. C57BL/6 mice received 100µL PBS. Colon tissues were collected at 3 and 60 days post MSC administration to evaluate the short-term and long-term effects of MSCs on inflammation and enteric neuropathy by histological and immunohistochemical analyses. In a separate set of experiments, multiple treatments with 4 × 106 and 2 × 106 MSCs were performed and tissue collected at 3 days post treatment. Chronic intestinal inflammation in Winnie mice was associated with persistent diarrhea, perianal bleeding, morphological changes, and immune cell infiltration in the colon. Significant changes to the ENS, including impairment of cholinergic, noradrenergic and sensory innervation, and myenteric neuronal loss were prominent in Winnie mice. Treatment with a single dose of bone marrow-derived MSCs was ineffective in attenuating chronic inflammation and enteric neuropathy in Winnie.
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Affiliation(s)
- Ainsley M Robinson
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Sarah Miller
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rajaraman Eri
- University of Tasmania, School of Health Sciences, Launceston, TAS, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia.
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17
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Qi L, Wu J, Zhu S, Wang X, Lv X, Liu C, Liu YJ, Chen J. Mesenchymal Stem Cells Alleviate Inflammatory Bowel Disease Via Tr1 Cells. Stem Cell Rev Rep 2022; 18:2444-2457. [PMID: 35274217 DOI: 10.1007/s12015-022-10353-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2022] [Indexed: 01/08/2023]
Abstract
Mesenchymal stem cells (MSCs) have been used to achieve exciting therapeutic outcomes in many animal studies and clinical trials for various autoimmune diseases, including inflammatory bowel disease (IBD). Type 1 regulatory T (Tr1) cells are the main source of interleukin (IL) 10 in the intestine. Whether Tr1 cells are involved during MSC-mediated IBD treatment is unclear. We treated a murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with human umbilical cord-derived MSCs (hUCMSCs) and found that the disease severity was alleviated significantly in a dose-dependent manner. hUCMSCs increased the proportion of Tr1 cells and decreased that of T helper (Th)-1 and Th17 cells in the spleen and mesenteric lymph nodes in different stages of colitis. We found that the upregulation of Tr1 cells by hUCMSCs was abrogated after blocking indoleamine-2,3-dioxygenase (IDO), and IDO knockdown in hUCMSCs reversed the increase in Tr1 cell proportions caused by hUCMSCs in colitis. Moreover, hUCMSCs inhibited apoptosis and promoted the proliferation of Tr1 cells. Our results suggest that Tr1 cells play an important role in the amelioration of IBD by MSCs, and they are the target population for the alleviation of IBD by MSCs, providing meaningful references for the study of therapeutic mechanisms of MSCs in other inflammatory diseases.
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Affiliation(s)
- Lingli Qi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China.,Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Jing Wu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China
| | - Shan Zhu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China
| | - Xue Wang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China.,Department of Jilin City Institute of Biological Products, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Jilin, China
| | - Xinping Lv
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China
| | - Chunyan Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China
| | - Yong-Jun Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China.
| | - Jingtao Chen
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China.
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18
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Das UN. Arachidonic Acid as Mechanotransducer of Renin Cell Baroreceptor. Nutrients 2022; 14:nu14040749. [PMID: 35215399 PMCID: PMC8874622 DOI: 10.3390/nu14040749] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 11/16/2022] Open
Abstract
For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell’s nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St., Battle Ground, WA 98604, USA
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19
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Essential Fatty Acids and Their Metabolites in the Pathobiology of Inflammation and Its Resolution. Biomolecules 2021; 11:biom11121873. [PMID: 34944517 PMCID: PMC8699107 DOI: 10.3390/biom11121873] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/22/2022] Open
Abstract
Arachidonic acid (AA) metabolism is critical in the initiation and resolution of inflammation. Prostaglandin E2 (PGE2) and leukotriene B4/D4/E4 (LTB4/LD4/LTE4), derived from AA, are involved in the initiation of inflammation and regulation of immune response, hematopoiesis, and M1 (pro-inflammatory) macrophage facilitation. Paradoxically, PGE2 suppresses interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production and triggers the production of lipoxin A4 (LXA4) from AA to initiate inflammation resolution process and augment regeneration of tissues. LXA4 suppresses PGE2 and LTs' synthesis and action and facilitates M2 macrophage generation to resolve inflammation. AA inactivates enveloped viruses including SARS-CoV-2. Macrophages, NK cells, T cells, and other immunocytes release AA and other bioactive lipids to produce their anti-microbial actions. AA, PGE2, and LXA4 have cytoprotective actions, regulate nitric oxide generation, and are critical to maintain cell shape and control cell motility and phagocytosis, and inflammation, immunity, and anti-microbial actions. Hence, it is proposed that AA plays a crucial role in the pathobiology of ischemia/reperfusion injury, sepsis, COVID-19, and other critical illnesses, implying that its (AA) administration may be of significant benefit in the prevention and amelioration of these diseases.
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20
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Li SW, Cai Y, Mao XL, He SQ, Chen YH, Yan LL, Zhou JJ, Song YQ, Ye LP, Zhou XB. The Immunomodulatory Properties of Mesenchymal Stem Cells Play a Critical Role in Inducing Immune Tolerance after Liver Transplantation. Stem Cells Int 2021; 2021:6930263. [PMID: 34531915 PMCID: PMC8440082 DOI: 10.1155/2021/6930263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/11/2021] [Accepted: 08/17/2021] [Indexed: 12/29/2022] Open
Abstract
Although liver transplantation is considered to be the best choice for patients with end-stage liver diseases, postoperative immune rejection still cannot be overlooked. Patients with liver transplantation have to take immunosuppressive drugs for a long time or even their entire lives, in which heavy economic burden and side effects caused by the drugs have become the major impediment for liver transplantation. There is a growing body of evidences indicating that mesenchymal stem cell (MSC) transplantation, a promising tool in regenerative medicine, can be used as an effective way to induce immune tolerance after liver transplantation based on their huge expansion potential and unique immunomodulatory properties. MSCs have been reported to inhibit innate immunity and adaptive immunity to induce a tolerogenic microenvironment. In in vitro studies, transplanted MSCs show plasticity in immune regulation by altering their viability, migration, differentiation, and secretion in the interactions with the surrounding host microenvironment. In this review, we aim to provide an overview of the current understanding of immunomodulatory properties of MSCs in liver transplantation, to elucidate the potential mechanisms behind MSCs regulating immune response, especially in vivo and the influence of the microenvironment, and ultimately to discuss the feasible strategies to improve the clinical prognosis of liver transplantation. Only after exhaustive understanding of potential mechanisms of the MSC immunomodulation can we improve the safety and effectiveness of MSC treatment and achieve better therapeutic effects.
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Affiliation(s)
- Shao-wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yue Cai
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xin-li Mao
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Sai-qin He
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ling-ling Yan
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Jing-jing Zhou
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ya-qi Song
- Taizhou Hospital, Zhejiang University, Linhai, Zhejiang, China
| | - Li-ping Ye
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xian-bin Zhou
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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21
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Park SG, An JH, Li Q, Chae HK, Park SM, Lee JH, Ahn JO, Song WJ, Youn HY. Feline adipose tissue-derived mesenchymal stem cells pretreated with IFN-γ enhance immunomodulatory effects through the PGE₂ pathway. J Vet Sci 2021; 22:e16. [PMID: 33774932 PMCID: PMC8007449 DOI: 10.4142/jvs.2021.22.e16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 12/12/2020] [Accepted: 01/07/2021] [Indexed: 01/03/2023] Open
Abstract
Background Preconditioning with inflammatory stimuli is used to improve the secretion of anti-inflammatory agents in stem cells from variant species such as mouse, human, and dog. However, there are only few studies on feline stem cells. Objectives This study aimed to evaluate the immune regulatory capacity of feline adipose tissue-derived (fAT) mesenchymal stem cells (MSCs) pretreated with interferon-gamma (IFN-γ). Methods To assess the interaction of lymphocytes and macrophages with IFN-γ-pretreated fAT-MSCs, mouse splenocytes and RAW 264.7 cells were cultured with the conditioned media from IFN-γ-pretreated MSCs. Results Pretreatment with IFN-γ increased the gene expression levels of cyclooxygenase-2, indoleamine 2,3-dioxygenase, hepatocyte growth factor, and transforming growth factor-beta 1 in the MSCs. The conditioned media from IFN-γ-pretreated MSCs increased the expression levels of M2 macrophage markers and regulatory T-cell markers compared to those in the conditioned media from naive MSCs. Further, prostaglandin E2 (PGE2) inhibitor NS-398 attenuated the immunoregulatory potential of MSCs, suggesting that the increased PGE2 levels induced by IFN-γ stimulation is a crucial factor in the immune regulatory capacity of MSCs pretreated with IFN-γ. Conclusions IFN-γ pretreatment improves the immune regulatory profile of fAT-MSCs mainly via the secretion of PGE2, which induces macrophage polarization and increases regulatory T-cell numbers.
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Affiliation(s)
- Seol Gi Park
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Ju Hyun An
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Qiang Li
- Department of Veterinary Medicine, College of Agriculture, Yanbian University, Yanji, Jilin 133000, China
| | - Hyung Kyu Chae
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Su Min Park
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Jeong Hwa Lee
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Jin Ok Ahn
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Woo Jin Song
- Department of Veterinary Internal Medicine, College of Veterinary Medicine and Research Institute of Veterinary Science, Jeju National University, Jeju 63243, Korea.
| | - Hwa Young Youn
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
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22
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Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, Yu J, Cao H. Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther 2021; 12:463. [PMID: 34407875 PMCID: PMC8375136 DOI: 10.1186/s13287-021-02533-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS Stem cell transplantation is a valuable supplementary therapy for CD.
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Affiliation(s)
- Ruo Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Pan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
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23
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Das UN. Molecular biochemical aspects of salt (sodium chloride) in inflammation and immune response with reference to hypertension and type 2 diabetes mellitus. Lipids Health Dis 2021; 20:83. [PMID: 34334139 PMCID: PMC8327432 DOI: 10.1186/s12944-021-01507-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/14/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and hypertension (HTN) are common that are associated with low-grade systemic inflammation. Diet, genetic factors, inflammation, and immunocytes and their cytokines play a role in their pathobiology. But the exact role of sodium, potassium, magnesium and other minerals, trace elements and vitamins in the pathogenesis of HTN and T2DM is not known. Recent studies showed that sodium and potassium can modulate oxidative stress, inflammation, alter the autonomic nervous system and induce dysfunction of the innate and adaptive immune responses in addition to their action on renin-angiotensin-aldosterone system. These actions of sodium, potassium and magnesium and other minerals, trace elements and vitamins are likely to be secondary to their action on pro-inflammatory cytokines IL-6, TNF-α and IL-17 and metabolism of essential fatty acids that may account for their involvement in the pathobiology of insulin resistance, T2DM, HTN and autoimmune diseases.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA, 98604, USA.
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24
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Das UN. Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections. Arch Med Sci 2021; 19:1327-1359. [PMID: 37732033 PMCID: PMC10507771 DOI: 10.5114/aoms/135703] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/11/2021] [Indexed: 09/22/2023] Open
Abstract
COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, γ-linolenic acid (GLA, dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19.
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Affiliation(s)
- Undurti N. Das
- UND Life Sciences, Battle Ground, WA, USA
- Department of Medicine, Omega Hospitals, Gachibowli, Hyderabad, India
- International Research Centre, Biotechnologies of the third Millennium, ITMO University, Saint-Petersburg, Russia
- Department of Biotechnology, Indian Institute of Technology-Hyderabad, Telangana, India
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25
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Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy. Front Cell Dev Biol 2021; 9:654885. [PMID: 33869217 PMCID: PMC8044970 DOI: 10.3389/fcell.2021.654885] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.
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Affiliation(s)
| | | | - Gerlinde R. Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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26
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Das UN. "Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications. Biomolecules 2021; 11:biom11020241. [PMID: 33567774 PMCID: PMC7914625 DOI: 10.3390/biom11020241] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/28/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.
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Affiliation(s)
- Undurti N. Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA; ; Tel.: +508-904-5376
- BioScience Research Centre and Department of Medicine, GVP Medical College and Hospital, Visakhapatnam 530048, India
- International Research Centre, Biotechnologies of the third Millennium, ITMO University, 191002 Saint-Petersburg, Russia
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27
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Seo MS, Kang KK, Oh SK, Sung SE, Kim KS, Kwon YS, Yun S. Isolation and Characterization of Feline Wharton's Jelly-Derived Mesenchymal Stem Cells. Vet Sci 2021; 8:vetsci8020024. [PMID: 33562192 PMCID: PMC7915203 DOI: 10.3390/vetsci8020024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Wharton’s jelly is a well-known mesenchymal stem cell source in many species, including humans. However, there have been no reports confirming the presence of mesenchymal stem cells in Wharton’s jelly in cats. The purpose of this study was to isolate mesenchymal stem cells (MSCs) from the Wharton’s jelly of cats and to characterize stem cells. In this study, feline Wharton’s jelly-derived mesenchymal stem cells (fWJ-MSCs) were isolated and successfully cultured. fWJ-MSCs were maintained and the proliferative potential was measured by cumulative population doubling level (CPDL) test, scratch test, and colony forming unit (CFU) test. Stem cell marker, karyotyping and immunophenotyping analysis by flow cytometry showed that fWJ-MSCs possessed characteristic mesenchymal stem cell markers. To confirm the differentiation potential, we performed osteogenic, adipogenic and chondrogenic induction under each differentiation condition. fWJ-MSCs has the ability to differentiate into multiple lineages, including osteogenic, adipogenic and chondrogenic differentiation. This study shows that Wharton’s jelly of cat can be a good source of mesenchymal stem cells. In addition, fWJ-MSCs may be useful for stem cell-based therapeutic applications in feline medicine.
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Affiliation(s)
- Min-Soo Seo
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; (M.-S.S.); (K.-K.K.); (S.-K.O.); (S.-E.S.); (K.-S.K.)
| | - Kyung-Ku Kang
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; (M.-S.S.); (K.-K.K.); (S.-K.O.); (S.-E.S.); (K.-S.K.)
| | - Se-Kyung Oh
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; (M.-S.S.); (K.-K.K.); (S.-K.O.); (S.-E.S.); (K.-S.K.)
| | - Soo-Eun Sung
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; (M.-S.S.); (K.-K.K.); (S.-K.O.); (S.-E.S.); (K.-S.K.)
| | - Kil-Soo Kim
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; (M.-S.S.); (K.-K.K.); (S.-K.O.); (S.-E.S.); (K.-S.K.)
- Department of Veterinary Toxicology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
| | - Young-Sam Kwon
- Department of Veterinary Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
- Correspondence: (Y.-S.K.); (S.Y.); Tel.: +82 53-950-5963 (S.Y.); Fax: +82-52-950-5955 (S.Y.)
| | - Sungho Yun
- Department of Veterinary Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
- Correspondence: (Y.-S.K.); (S.Y.); Tel.: +82 53-950-5963 (S.Y.); Fax: +82-52-950-5955 (S.Y.)
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28
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Proteomic Analysis of the Secretome and Exosomes of Feline Adipose-Derived Mesenchymal Stem Cells. Animals (Basel) 2021; 11:ani11020295. [PMID: 33498940 PMCID: PMC7912403 DOI: 10.3390/ani11020295] [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: 12/04/2020] [Revised: 01/14/2021] [Accepted: 01/21/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The enormous advances in stem cell research have generated high expectations in the development of new therapies to repair or regenerate damaged tissues. For this reason, laboratory studies of stem cells enable scientists to learn about cells’ essential properties. Specifically, in recent years, therapies based on mesenchymal stem cells have become an interesting alternative for the treatment of different complex pathologies in veterinary medicine. Mesenchymal stem cells secrete a wide variety of therapeutic elements such as bioactive molecules and extracellular vesicles (e.g., exosomes). Thus, it is essential to characterize them before future use as biotechnological products. Therefore, the objective of this study was to determine and compare their protein profile to understand better the mechanisms of action of these components and facilitate their possible use in future therapies. The data demonstrate the existence of different proteins responsible for the biological effects of cells. In addition, these approaches and techniques can contribute to the better prediction of clinical outcomes of mesenchymal stem cell treatment. Abstract Mesenchymal stem cells (MSCs) have been shown to have therapeutic efficacy in different complex pathologies in feline species. This effect is attributed to the secretion of a wide variety of bioactive molecules and extracellular vesicles, such as exosomes, with significant paracrine activity, encompassed under the concept of the secretome. However, at present, the exosomes from feline MSCs have not yet been studied in detail. The objective of this study is to analyze and compare the protein profiles of the secretome as a whole and its exosomal fraction from feline adipose-derived MSCs (fAd-MSCs). For this, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein–Protein Interaction Networks Functional Enrichment Analysis (STRING) were utilized. A total of 239 proteins were identified in the secretome, and 228 proteins specific to exosomes were identified, with a total of 133 common proteins. The proteins identified in the secretome were located in the extracellular regions and in the cytoplasm, while the exosomal proteins were located mainly in the membrane, cytoplasm and cytosol. Regarding function, in the secretome, proteins involved in different metabolic pathways, in pathways related to the immune system and the endocrine system and in the processing of proteins in the endoplasmic reticulum predominated. In contrast, proteins specific to exosomes were predominantly associated with endocytosis, cell junctions, platelet activation and other cell signaling pathways. The possible future use of the secretome, or some of its components, such as exosomes, would provide a non-cell-based therapeutic strategy for the treatment of different diseases that would avoid the drawbacks of cell therapy.
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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.
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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
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30
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Das UN. Bioactive Lipids as Mediators of the Beneficial Action(s) of Mesenchymal Stem Cells in COVID-19. Aging Dis 2020; 11:746-755. [PMID: 32765941 PMCID: PMC7390526 DOI: 10.14336/ad.2020.0521] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022] Open
Abstract
It is proposed that the beneficial action of mesenchymal stem cells (MSCs) in COVID-19 and other inflammatory diseases could be attributed to their ability to secrete bioactive lipids (BALs) such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) and other similar BALs. This implies that MSCs that have limited or low capacity to secrete BALs may be unable to bring about their beneficial actions. This proposal implies that pretreatment of MSCs with BALs enhance their physiological action or improve their (MSCs) anti-inflammatory and disease resolution capacity to a significant degree. Thus, the beneficial action of MSCs reported in the management of COVID-19 could be attributed to their ability to secrete BALs, especially PGE2 and LXA4. Since PGE2, LXA4 and their precursors AA (arachidonic acid), dihomo-gamma-linolenic acid (DGLA) and gamma-linolenic acid (GLA) inhibit the production of pro-inflammatory IL-6 and TNF-α, they could be employed to treat cytokine storm seen in COVID-19, immune check point inhibitory (ICI) therapy, sepsis and ARDS (acute respiratory disease). This is further supported by the observation that GLA, DGLA and AA inactivate enveloped viruses including COVID-19. Thus, infusions of appropriate amounts of GLA, DGLA, AA, PGE2 and LXA4 are of significant therapeutic benefit in COVID-19, ICI therapy and other inflammatory conditions including but not limited to sepsis. AA is the precursor of both PGE2 and LXA4 suggesting that AA is most suited for such preventive and therapeutic approach.
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Affiliation(s)
- Undurti N Das
- 1UND Life Sciences, Battle Ground, WA 98604, USA.,2BioScience Research Centre and Department of Medicine, Gayatri Vidya Parishad Medical College and Hospital, Visakhapatnam-530048, India
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The Achievements and Challenges of Mesenchymal Stem Cell-Based Therapy in Inflammatory Bowel Disease and Its Associated Colorectal Cancer. Stem Cells Int 2020; 2020:7819824. [PMID: 32256612 PMCID: PMC7104387 DOI: 10.1155/2020/7819824] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/07/2020] [Accepted: 02/03/2020] [Indexed: 02/08/2023] Open
Abstract
Approximately 18.1 × 106 new cases of cancer were recorded globally in 2018, out of which 9.6 million died. It is known that people who have Inflammatory Bowel Disease (IBD) turn to be prone to increased risks of developing colorectal cancer (CRC), which has global incident and mortality rates of 10.2% and 9.2%, respectively. Over the years, conventional treatments of IBD and its associated CRC have been noted to provide scarce desired results and often with severe complications. The introduction of biological agents as a better therapeutic approach has witnessed a great deal of success in both experimental and clinical models. With regard to mesenchymal stem cell (MSC) therapy, the ability of these cells to actively proliferate, undergo plastic differentiation, trigger strong immune regulation, exhibit low immunogenicity, and express abundant trophic factors has ensured their success in regenerative medicine and immune intervention therapies. Notwithstanding, MSC-based therapy is still confronted with some challenges including the likelihood of promoting tumor growth and metastasis, and possible overestimated therapeutic potentials. We review the success story of MSC-based therapy in IBD and its associated CRC as documented in experimental models and clinical trials, examining some of the challenges encountered and possible ways forward to producing an optimum MSC therapeutic imparts.
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Hao X, Gao M, He L, Ye X, Yang J, Zhang F, Liu R, Wei H. Deficiency of O-linked-glycosylation regulates activation of T cells and aggravates Concanavalin A-induced liver injury. Toxicology 2020; 433-434:152411. [PMID: 32081641 DOI: 10.1016/j.tox.2020.152411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 01/16/2020] [Accepted: 02/16/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Protein glycosylation is involved in immunological recognition and immune cell activation. The role of O-glycosylation in Concanavalin A (Con A)-induced autoimmune hepatitis (AIH) was elucidated in the present study. METHODS Mice were intravenously injected with Con A (10 mg/kg) to establish an AIH mouse model. Here, 24 h prior to administration of Con A, experimental mice were intragastrically administrated with O-glycosylation inhibitor (benzyl-α-GalNAc) at doses of 1 and 5 mg/kg, respectively, while control mice were administrated with the same volume of saline. Before and after administration of Con A for 6 and 12 h, mice were sacrificed and their plasma and livers were collected to score liver injury. Peripheral blood, spleen, and thymus were collected for flow cytometry analysis. The expression levels of neutrophilic alkaline phosphatase-3 (NALP3) and NALP6 in liver were evaluated as well. RESULTS Pre-treatment with benzyl-α-GalNAc increased the serum transaminase levels and induced more infiltration and necrosis in livers of Con A administrated mice. The levels of some pro-inflammation cytokines also increased in administrated mice. In addition, pretreatment with benzyl-α-GalNAc up-regulated the expression levels of NALP3 and NALP6. And benzyl-α-GalNAc inhibited the levels of apoptosis of thymus cells and influenced activation of T cells in peripheral blood and spleen of Con A administrated mice, especially that accelerated the physiological progression of CD4+CD25-CD69+ subset. CONCLUSION The present research demonstrated that benzyl-α-GalNAc aggravated Con A-induced AIH, and the role of the O-glycosylation inhibitor as the aggravation may be related to regulation of the levels of cytokines, as well as influencing proliferation of T cells.
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Affiliation(s)
- Xiaohua Hao
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Meixin Gao
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Lingling He
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Xiaohui Ye
- Department of Gastroenterology, Beijing Huaxin Hospital, the First Affiliated Hospital of Tsinghua Uinversity, A Neighborhood of No.6, Jiuxianqiao, Chaoyang District, Beijing, 100016, China.
| | - Junru Yang
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Fuyang Zhang
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Ran Liu
- Miyun Education Hospital, Capital Medicine University, No. 383 Yangguang Street, Miyun District, Beijing, 101500, China.
| | - Hongshan Wei
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China; Department of Gastroenterology, Peking University Ditan Teaching Hospital, No. 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
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TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis. PLoS One 2020; 15:e0220756. [PMID: 32040478 PMCID: PMC7010233 DOI: 10.1371/journal.pone.0220756] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue derived mesenchymal stem/stromal cell (ASC)-derived extracellular vesicles (EV) have been reported to be beneficial against dextran sulfate sodium (DSS)-induced colitis in mice. However, the underlying mechanisms have not been fully elucidated. We hypothesize that the tumor necrosis factor-α-stimulated gene/protein 6 (TSG-6) in EVs is a key factor influencing the alleviation of colitis symptoms. DSS-induced colitis mice (C57BL/6, male, Naïve = 6, Sham = 8, PBS = 8 EV = 8, CTL-EV = 8, TSG-6 depleted EV = 8) were intraperitoneally administered EVs (100 ug/mice) on day 1, 3, and 5; colon tissues were collected on day 10 for histopathological, RT-qPCR, western blot and immunofluorescence analyses. In mice injected with EV, inflammation was alleviated. Indeed, EVs regulated the levels of pro- and anti-inflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, IL-6, and IL-10 in inflamed colons. However, when injected with TSG-6 depleted EV, the degree of inflammatory relief was reduced. Furthermore, TSG-6 in EVs plays a key role in increasing regulatory T cells (Tregs) and polarizing macrophage from M1 to M2 in the colon. In conclusion, this study shows that TSG-6 in EVs is a major factor in the relief of DSS-induced colitis, by increasing the number of Tregs and macrophage polarization from M1 to M2 in the colon.
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TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis. Sci Rep 2020; 10:2115. [PMID: 32034203 PMCID: PMC7005871 DOI: 10.1038/s41598-020-58909-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022] Open
Abstract
The inflammatory bowel diseases (IBD) are characterized by relapsing inflammation and immune activation diseases of the gastrointestinal tract. Extracellular vesicles, which elicit similar biological activity to the stem cell themselves, have been used experimentally to treat dextran sulfate sodium (DSS)-induced colitis in murine models though immunosuppressive potential. In this study, we investigated whether the Extracellular vesicles (EVs) obtained by stimulating inflammatory cytokine on canine adipose mesenchymal stem cells (cASC) improved anti-inflammatory and/or immunosuppressive potential of EVs, and/or their ability to alleviate inflammation in colitis. We also explored the correlation between immune cells and the inflammatory repressive effect of primed EVs. Pro-inflammatory cytokines such as TNF-α and IFN-γ increased immunosuppressive protein such as HGF, TSG-6, PGE2 and TGF-β in EVs. Moreover, the anti-inflammatory effect of EVs was improved through pretreatment with inflammatory cytokines. Importantly, EVs obtained from primed stem cells effectively induced macrophage polarization toward an anti-inflammatory M2 phenotype and suppressed activated immunity by enhancing regulatory T cells in inflamed colon in mice. Our results provide a new and effective therapy for the EVs obtained from ASC stimulated with TNF-α and IFN-γ against not only IBD, but also immune-mediated disease.
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Negi N, Griffin MD. Effects of mesenchymal stromal cells on regulatory T cells: Current understanding and clinical relevance. Stem Cells 2020; 38:596-605. [PMID: 31995249 PMCID: PMC7217190 DOI: 10.1002/stem.3151] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/13/2020] [Indexed: 12/13/2022]
Abstract
The immunomodulatory potential of mesenchymal stromal cells (MSCs) and regulatory T cells (T‐reg) is well recognized by translational scientists in the field of regenerative medicine and cellular therapies. A wide range of preclinical studies as well as a limited number of human clinical trials of MSC therapies have not only shown promising safety and efficacy profiles but have also revealed changes in T‐reg frequency and function. However, the mechanisms underlying this potentially important observation are not well understood and, consequently, the optimal strategies for harnessing MSC/T‐reg cross‐talk remain elusive. Cell‐to‐cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes, and induction of extracellular vesicles (“exosomes”) have emerged as possible mechanisms by which MSCs produce an immune‐modulatory milieu for T‐reg expansion. Additionally, these two cell types have the potential to complement each other's immunoregulatory functions, and a combinatorial approach may exert synergistic effects for the treatment of immunological diseases. In this review, we critically assess recent translational research related to the outcomes and mechanistic basis of MSC effects on T‐reg and provide a perspective on the potential for this knowledge base to be further exploited for the treatment of autoimmune disorders and transplants.
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Affiliation(s)
- Neema Negi
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, Ireland
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Dual-Functionalized MSCs that Express CX3CR1 and IL-25 Exhibit Enhanced Therapeutic Effects on Inflammatory Bowel Disease. Mol Ther 2020; 28:1214-1228. [PMID: 32087149 DOI: 10.1016/j.ymthe.2020.01.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 01/15/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have shown great promise in inflammatory bowel disease (IBD) treatment, owing to their immunosuppressive capabilities, but their therapeutic effectiveness is sometimes thwarted by their low efficiency in entering the inflamed colon and variable immunomodulatory ability in vivo. Here, we demonstrated a new methodology to manipulate MSCs to express CX3C chemokine receptor 1 (CX3CR1) and interleukin-25 (IL-25) to promote their delivery to the inflamed colon and enhance their immunosuppressive capability. Compared to MSCs without treatment, MSCs infected with a lentivirus (LV) encoding CX3CR1 and IL-25 (CX3CR1&IL-25-LV-MSCs) exhibited enhanced targeting to the inflamed colon and could further move into extravascular space of the colon tissues via trans-endothelial migration in dextran sodium sulfate (DSS)-challenged mice after MSC intravenous injection. The administration of the CX3CR1&IL-25-LV-MSCs achieved a better therapeutic effect than that of the untreated MSCs, as indicated by pathological indices and inflammatory markers. Antibody-blocking studies indicated that the enhanced therapeutic effects of dual-functionalized MSCs were dependent on CX3CR1 and IL-25 function. Overall, this strategy, which is based on enhancing the homing and immunosuppressive abilities of MSCs, represents a promising therapeutic approach that may be valuable in IBD therapy.
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You Y, Wen DG, Gong JP, Liu ZJ. Research Status of Mesenchymal Stem Cells in Liver Transplantation. Cell Transplant 2019; 28:1490-1506. [PMID: 31512503 PMCID: PMC6923564 DOI: 10.1177/0963689719874786] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liver transplantation has been deemed the best choice for end-stage liver disease
patients but immune rejection after surgery is still a serious problem. Patients have to
take immunosuppressive drugs for a long time after liver transplantation, and this often
leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to
researchers because of their powerful immunomodulatory effects. In the past, a large
number of in vitro and in vivo studies have demonstrated the great potential of MSCs for
participation in posttransplant immunomodulation. In addition, MSCs also have properties
that may potentially benefit patients undergoing liver transplantation. This article aims
to provide an overview of the current understanding of the immunomodulation achieved by
the application of MSCs in liver transplantation, to discuss the problems that may be
encountered when using MSCs in clinical practice, and to describe some of the underlying
capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and
exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro;
however, the exact mechanism, especially in vivo, is still unclear. In recent years, the
clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to
the clinical application of MSCs are decreasing, but large sample clinical trials
involving MSCs are still needed to further study their clinical effects.
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Affiliation(s)
- Yu You
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, China.,Yu You and Di-guang Wen are equal contributors and co-first authors of this article
| | - Di-Guang Wen
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, China.,Yu You and Di-guang Wen are equal contributors and co-first authors of this article
| | - Jian-Ping Gong
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, China
| | - Zuo-Jin Liu
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, China
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