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1
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Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
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Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
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2
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Lee DH, Han JW, Park H, Hong SJ, Kim CS, Kim YS, Lee IS, Kim GJ. Achyranthis radix Extract Enhances Antioxidant Effect of Placenta-Derived Mesenchymal Stem Cell on Injured Human Ocular Cells. Cells 2024; 13:1229. [PMID: 39056810 PMCID: PMC11274440 DOI: 10.3390/cells13141229] [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: 06/20/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases.
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Affiliation(s)
- Dae-Hyun Lee
- Department of Biomedical Science, CHA University, Seongnam 13488, Republic of Korea; (D.-H.L.); (H.P.); (S.J.H.)
| | - Ji Woong Han
- Advanced PLAB, PLABiologics Co., Ltd., Seongnam 13522, Republic of Korea;
| | - Hyeri Park
- Department of Biomedical Science, CHA University, Seongnam 13488, Republic of Korea; (D.-H.L.); (H.P.); (S.J.H.)
| | - Se Jin Hong
- Department of Biomedical Science, CHA University, Seongnam 13488, Republic of Korea; (D.-H.L.); (H.P.); (S.J.H.)
| | - Chan-Sik Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (C.-S.K.); (Y.S.K.)
| | - Young Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (C.-S.K.); (Y.S.K.)
| | - Ik Soo Lee
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (C.-S.K.); (Y.S.K.)
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam 13488, Republic of Korea; (D.-H.L.); (H.P.); (S.J.H.)
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3
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Xie Q, Gu J. Therapeutic and Safety Promise of Mesenchymal Stem Cells for Liver Failure: From Preclinical Experiment to Clinical Application. Curr Stem Cell Res Ther 2024; 19:1351-1368. [PMID: 37807649 DOI: 10.2174/011574888x260690230921174343] [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: 05/04/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 10/10/2023]
Abstract
Liver failure (LF) is serious liver damage caused by multiple factors, resulting in severe impairment or decompensation of liver synthesis, detoxification, metabolism, and biotransformation. The general prognosis of LF is poor with high mortality in non-transplant patients. The clinical treatments for LF are mainly internal medicine comprehensive care, artificial liver support system, and liver transplantation. However, none of the above treatment strategies can solve the problems of all liver failure patients and has its own limitations. Mesenchymal stem cells (MSCs) are a kind of stem cells with multidirectional differentiation potential and paracrine function, which play an important role in immune regulation and tissue regeneration. In recent years, MSCs have shown multiple advantages in the treatment of LF in pre-clinical experiments and clinical trials. In this work, we reviewed the biological characteristics of MSCs, the possible molecular mechanisms of MSCs in the treatment of liver failure, animal experiments, and clinical application, and also discussed the existing problems of MSCs in the treatment of liver failure.
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Affiliation(s)
- Qiong Xie
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
| | - Jundong Gu
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
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Park H, Lee DH, You JH, Seok J, Lim JY, Kim GJ. Increased Hepatocyte Growth Factor Secretion by Placenta-Derived Mesenchymal Stem Cells Improves Ovarian Function in an Ovariectomized Rat Model via Vascular Remodeling by Wnt Signaling Activation. Cells 2023; 12:2708. [PMID: 38067136 PMCID: PMC10705748 DOI: 10.3390/cells12232708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
The vascular network contributes to the development of follicles. However, the therapeutic mechanism between vascular remodeling and ovarian functions is still unclear. Therefore, we demonstrated whether increased HGF by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in an ovariectomized rat model via vascular remodeling by Wnt signaling activation. We established a half-ovariectomized rat model in which damaged ovaries were induced by ovariectomy of half of each ovary, and PD-MSCs (5 × 105 cells) were transplanted by intravenous injection. Three weeks after transplantation, rats in all groups were sacrificed. We examined the secretion of HGF by PD-MSCs through culture medium. The vascular structure in injured ovarian tissues was restored to a greater extent in the PD-MSC transplantation (Tx) group than in the nontransplantation (NTx) group (* p < 0.05). The expression of genes related to Wnt signaling (e.g., LRP6, GSK3β, β-catenin) was significantly increased in the Tx group compared to the NTx group (* p < 0.05). However, the expression of genes related to vascular permeability (e.g., Asef, ERG3) was significantly decreased in the Tx group compared to the NTx group (* p < 0.05). Follicular development was improved in the Tx group compared to the NTx group (* p < 0.05). Furthermore, to evaluate vascular function, we cocultivated PD-MSCs after human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and we analyzed the vascular formation assay and dextran assay in HUVECs. Cocultivation of PD-MSCs with injured HUVECs enhanced vascular formation and decreased endothelial cell permeability (* p < 0.05). Also, cocultivation of PD-MSCs with explanted ovarian tissues improved follicular maturation compared to cocultivation of the Wnt inhibitor-treated PD-MSCs with explanted ovarian tissues. Therefore, HGF secreted by PD-MSCs improved ovarian function in rats with ovarian dysfunction by decreasing vascular permeability via Wnt signaling.
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Affiliation(s)
- Hyeri Park
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
- PLABiologics Co., Ltd., Seongnam-si 13522, Gyeonggi-do, Republic of Korea
| | - Dae Hyun Lee
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
- PLABiologics Co., Ltd., Seongnam-si 13522, Gyeonggi-do, Republic of Korea
| | - Jun Hyeong You
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
| | - Jin Seok
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
| | - Ja-Yun Lim
- Department of Clinical Laboratory Science, Hyejeon College, Hongsung-gun 32244, Chungnam-do, Republic of Korea
| | - Gi Jin Kim
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
- PLABiologics Co., Ltd., Seongnam-si 13522, Gyeonggi-do, Republic of Korea
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Zhao P, Sun T, Lyu C, Liang K, Du Y. Cell mediated ECM-degradation as an emerging tool for anti-fibrotic strategy. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:29. [PMID: 37653282 PMCID: PMC10471565 DOI: 10.1186/s13619-023-00172-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 07/10/2023] [Indexed: 09/02/2023]
Abstract
Investigation into the role of cells with respect to extracellular matrix (ECM) remodeling is still in its infancy. Particularly, ECM degradation is an indispensable process during the recovery from fibrosis. Cells with ECM degradation ability due to the secretion of various matrix metalloproteinases (MMPs) have emerged as novel contributors to the treatment of fibrotic diseases. In this review, we focus on the ECM degradation ability of cells associated with the repertoire of MMPs that facilitate the attenuation of fibrosis through the inhibition of ECM deposition. Besides, innovative approaches to engineering and characterizing cells with degradation ability, as well as elucidating the mechanism of the ECM degradation, are also illustrated. Studies conducted to date on the use of cell-based degradation for therapeutic purposes to combat fibrosis are summarized. Finally, we discuss the therapeutic potential of cells with high degradation ability, hoping to bridge the gap between benchside research and bedside applications in treating fibrotic diseases.
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Affiliation(s)
- Peng Zhao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Tian Sun
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Cheng Lyu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
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Shibu MA, Huang CY, Ding DC. Comparison of two hepatocyte differentiation protocols in human umbilical cord mesenchymal stem cells: In vitro study. Tissue Cell 2023; 83:102153. [PMID: 37413859 DOI: 10.1016/j.tice.2023.102153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/08/2023]
Abstract
Human umbilical cord mesenchymal stromal cells (HUCMSCs) are an emerging source of cell therapy due to their self-renew and differentiation ability. They can differentiate into three germ layers, including the potential to generate hepatocytes. This study determined the transplantation efficiency and suitability of HUCMSCs-derived hepatocyte-like cells (HLCs) for their therapeutic application for liver diseases. This study aims to formulate ideal conditions to induce HUCMSCs into the hepatic lineage and investigate the efficiency of the differentiated HLCs based on their expression characteristics and capacity to integrate into the damaged liver of CCl4-challenged mice. Hepatocyte growth factor (HGF) and Activin A, Wnt3a were found to optimally promote the endodermal expansion of HUCMSCs, which showed phenomenal expression of hepatic markers upon differentiation in the presence of oncostatin M and dexamethasone. HUCMSCs expressed MSC-related surface markers and could undergo tri-lineage differentiations. Two hepatogenic differentiation protocols (differentiated hepatocyte protocol 1 [DHC1]: 32 days and DHC2: 15 days) were experimented with. The proliferation rate was faster in DHC2 than in DHC1 on day 7 of differentiation. The migration capability was the same in both DHC1 and DHC2. Hepatic markers like CK18, CK19, ALB, and AFP were upregulated. The mRNA levels of albumin, α1AT, αFP, CK18, TDO2, CYP3A4, CYP7A1, HNF4A, CEBPA, PPARA, and PAH were even higher in the HUCMSCs-derived HCLs than in the primary hepatocytes. Western blot confirmed HNF3B and CK18 protein expression in a step-wise manner differentiated from HUCMSCs. The metabolic function of differentiated hepatocytes was evident by increasing PAS staining and urea production. Pre-treating HUCMSCs with a hepatic differentiation medium containing HGF can drive their differentiation towards endodermal and hepatic lineages, enabling efficient integration into the damaged liver. This approach represents a potential alternative protocol for cell-based therapy that could enhance the integration potential of HUCMSC-derived HLCs.
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Affiliation(s)
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biological Science and Technology, Asia University, Taichung 413, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University Hospital, Taichung 404, Taiwan
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan; Graduate Institute of Medical Science, Tzu Chi University, Hualien 970, Taiwan.
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Rosner M, Horer S, Feichtinger M, Hengstschläger M. Multipotent fetal stem cells in reproductive biology research. Stem Cell Res Ther 2023; 14:157. [PMID: 37287077 DOI: 10.1186/s13287-023-03379-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Due to the limited accessibility of the in vivo situation, the scarcity of the human tissue, legal constraints, and ethical considerations, the underlying molecular mechanisms of disorders, such as preeclampsia, the pathological consequences of fetomaternal microchimerism, or infertility, are still not fully understood. And although substantial progress has already been made, the therapeutic strategies for reproductive system diseases are still facing limitations. In the recent years, it became more and more evident that stem cells are powerful tools for basic research in human reproduction and stem cell-based approaches moved into the center of endeavors to establish new clinical concepts. Multipotent fetal stem cells derived from the amniotic fluid, amniotic membrane, chorion leave, Wharton´s jelly, or placenta came to the fore because they are easy to acquire, are not associated with ethical concerns or covered by strict legal restrictions, and can be banked for autologous utilization later in life. Compared to adult stem cells, they exhibit a significantly higher differentiation potential and are much easier to propagate in vitro. Compared to pluripotent stem cells, they harbor less mutations, are not tumorigenic, and exhibit low immunogenicity. Studies on multipotent fetal stem cells can be invaluable to gain knowledge on the development of dysfunctional fetal cell types, to characterize the fetal stem cells migrating into the body of a pregnant woman in the context of fetomaternal microchimerism, and to obtain a more comprehensive picture of germ cell development in the course of in vitro differentiation experiments. The in vivo transplantation of fetal stem cells or their paracrine factors can mediate therapeutic effects in preeclampsia and can restore reproductive organ functions. Together with the use of fetal stem cell-derived gametes, such strategies could once help individuals, who do not develop functional gametes, to conceive genetically related children. Although there is still a long way to go, these developments regarding the usage of multipotent fetal stem cells in the clinic should continuously be accompanied by a wide and detailed ethical discussion.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | - Stefanie Horer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | | | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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Kim WH, Yoo JH, Yoo IK, Kwon CI, Hong SP. Effects of Mesenchymal Stem Cells Treatment on Radiation-Induced Proctitis in Rats. Yonsei Med J 2023; 64:167-174. [PMID: 36825342 PMCID: PMC9971437 DOI: 10.3349/ymj.2022.0342] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 02/25/2023] Open
Abstract
PURPOSE There are no effective treatment methods with which to control complications of radiation proctitis with fistula or recurrent bleeding following radiation treatment for prostate, cervical, or rectal cancer. Mesenchymal stem cells (MSCs) can induce immune modification, resulting in tissue repair and regeneration. Therefore, we used a rat model of radiation-induced proctitis and observed the effects of using human placenta-derived (PD) and adipose tissue-derived (AD) MSCs. MATERIALS AND METHODS Female Sprague Dawley rats were irradiated at the pelvic area with 25 Gy. We injected 1×106 cells of human PD-MSCs, human AD-MSCs, human foreskin fibroblasts, and control media into the rectal submucosa following irradiation. We sacrificed rats for pathologic evaluation. RESULTS Fibrosis on the rectum was reduced in both MSC groups, compared to the control group. Mucosal Ki-67 indices of both MSC injected groups were higher than those in the control group. Although caspase-3 positive cells in the mucosa gradually increased and decreased in the control group, those in both MSC injected groups increased rapidly and decreased thereafter. CONCLUSION We demonstrated the effects of regional MSC injection treatment for radiation-induced proctitis in rats. MSC injection reduced fibrosis and increased proliferation in rat mucosa. Human AD-MSCs and PD-MSCs had similar effectiveness.
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Affiliation(s)
- Won Hee Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jun Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - In Kyung Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Chang Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
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Phosphatase of Regenerating Liver-1 (PRL-1)-Overexpressing Placenta-Derived Mesenchymal Stem Cells Enhance Antioxidant Effects via Peroxiredoxin 3 in TAA-Injured Rat Livers. Antioxidants (Basel) 2022; 12:antiox12010046. [PMID: 36670907 PMCID: PMC9855122 DOI: 10.3390/antiox12010046] [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: 11/02/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
DNA damage repair is induced by several factors and is critical for cell survival, and many cellular DNA damage repair mechanisms are closely linked. Antioxidant enzymes that control cytokine-induced peroxide levels, such as peroxiredoxins (Prxs) and catalase (CAT), are involved in DNA repair systems. We previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) that overexpress PRL-1 (PRL-1(+)) promote liver regeneration via antioxidant effects in TAA-injured livers. However, the efficacy of these cells in regeneration and the role of Prxs in their DNA repair system have not been reported. Therefore, our objective was to analyze the Prx-based DNA repair mechanism in naïve or PRL-1(+)-transplanted TAA-injured rat livers. Apoptotic cell numbers were significantly decreased in the PRL-1(+) transplantation group versus the nontransplantation (NTx) group (p < 0.05). The expression of antioxidant markers was significantly increased in PRL-1(+) cells compared to NTx cells (p < 0.05). MitoSOX and Prx3 demonstrated a significant negative correlation coefficient (R2 = −0.8123). Furthermore, DNA damage marker levels were significantly decreased in PRL-1(+) cells compared to NTx cells (p < 0.05). In conclusion, increased Prx3 levels in PRL-1(+) cells result in an effective antioxidant effect in TAA-injured liver disease, and Prx3 is also involved in repairing damaged DNA.
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Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function? Int J Mol Sci 2022; 23:ijms232416009. [PMID: 36555651 PMCID: PMC9788312 DOI: 10.3390/ijms232416009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 105) and high (5 × 105) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p < 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p < 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems.
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12
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Shen LH, Fan L, Zhang Y, Zhu YK, Zong XL, Peng GN, Cao SZ. Protective Effect and Mechanism of Placenta Extract on Liver. Nutrients 2022; 14:nu14235071. [PMID: 36501102 PMCID: PMC9737791 DOI: 10.3390/nu14235071] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
The placenta contains multiple biologically active substances, which exert antioxidation, anti-inflammatory, immunomodulatory, and delayed aging effects. Its extract can improve hepatic morphology and function: on the one hand, it can reduce liver interstitial collagen deposition, lipogenesis, and inflammatory cell infiltration and improve fibrosis; on the other hand, it can prevent hepatocellular degeneration by scavenging reactive oxygen species (ROS) and inhibiting inflammatory cytokine production, further improve hepatocyte apoptosis and necrosis, and promote hepatocyte regeneration, making it a promising liver-protective agent. Current research on placenta extract (PE) mainly focuses on treating a specific type of liver injury, and there are no systematic reports. Therefore, this review comprehensively summarizes the treatment reports of PE on liver injury and analyzes its mechanism of action.
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Affiliation(s)
- Liu-Hong Shen
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Correspondence: ; Tel.: +86-181-0901-7590
| | - Lei Fan
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yue Zhang
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Ying-Kun Zhu
- School of Agriculture & Food Science, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Xiao-Lan Zong
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Guang-Neng Peng
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Sui-Zhong Cao
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, The Medical Research Center for Cow Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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13
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Pozzobon M, D’Agostino S, Roubelakis MG, Cargnoni A, Gramignoli R, Wolbank S, Gindraux F, Bollini S, Kerdjoudj H, Fenelon M, Di Pietro R, Basile M, Borutinskaitė V, Piva R, Schoeberlein A, Eissner G, Giebel B, Ponsaerts P. General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications. Front Bioeng Biotechnol 2022; 10:961987. [PMID: 36263355 PMCID: PMC9574482 DOI: 10.3389/fbioe.2022.961987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Stefania D’Agostino
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Maria G. Roubelakis
- Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, The Research Center in Cooperation with AUVA Trauma Research Center, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et plastique, CHU Besançon, Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, University Bourgogne Franche-Comté, Besançon, France
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Halima Kerdjoudj
- University of Reims Champagne Ardenne, EA 4691 BIOS “Biomatériaux et Inflammation en Site Osseux”, UFR d’Odontologie, Reims, France
| | | | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Mariangela Basile
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Veronika Borutinskaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
| | - Roberta Piva
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Guenther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
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14
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Interleukin-10-Modified Adipose-Derived Mesenchymal Stem Cells Prevent Hypertrophic Scar Formation via Regulating the Biological Characteristics of Fibroblasts and Inflammation. Mediators Inflamm 2022; 2022:6368311. [PMID: 35774067 PMCID: PMC9239815 DOI: 10.1155/2022/6368311] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022] Open
Abstract
Hypertrophic scar causes serious functional and cosmetic problem, but no treatment method is known to achieve a satisfactory therapeutic effect. However, mesenchymal stem cells show a possible cure prospect. Here, we investigated the effect of interleukin-10-modified adipose-derived mesenchymal stem cells (IL-10-ADMSC) on the formation of hypertrophic scar. In vitro, IL-10-ADMSC could highly express IL-10 and exhibited stronger inhibition of hypertrophic scar fibroblasts (HSFs) proliferation, migration, and extracellular matrix synthesis (the expression of collagen I, collagen III, FN, and α-SMA protein) than ADMSC. In vivo, we found that IL-10-ADMSC speeded up wound healing time and reduced scar area and scar outstanding height. Same as in vitro, IL-10-ADMSC also exhibited stronger inhibition of extracellular matrix synthesis (the expression of collagen I, collagen III protein) in wound than ADMSC. In addition, we also found that IL-10-ADMSC is also a stronger inhibitory effect on inflammation in wound than ADMSC, and IL-10-ADMSC inhibited TGF-β/Smads and NF-κB pathway. In conclusion, IL-10-ADMSC demonstrated the ability to prevent hypertrophic scar formation. And its possible molecular mechanism might be related to IL-10-ADMSC inhibiting the proliferation and migration of the synthesis of extracellular matrix of HSFs, and IL-10-ADMSC inhibited the inflammation during the wound healing.
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15
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Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products. Cells 2022; 11:cells11071074. [PMID: 35406638 PMCID: PMC8997603 DOI: 10.3390/cells11071074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/04/2023] Open
Abstract
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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16
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Park H, Seok J, You JH, Kim JY, Lim JY, Kim GJ. Increased phosphatase regenerating liver-1 trigger vascular remodeling in injured ovary via platelet-derived growth factor signaling pathway. Stem Cell Res Ther 2022; 13:95. [PMID: 35255961 PMCID: PMC8900363 DOI: 10.1186/s13287-022-02772-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/26/2021] [Indexed: 11/10/2022] Open
Abstract
Background Vascular abnormalities in the ovary cause infertility accompanied by ovarian insufficiency due to a microenvironment of barren ovarian tissues. Placenta-derived mesenchymal stem cells (PD-MSCs, Naïve) treatment in ovarian dysfunction shows angiogenic effect, however, the therapeutic mechanism between ovarian function and vascular remodeling still unclear. Therefore, we examined whether by phosphatase regenerating liver-1 (PRL-1), which is correlated with angiogenesis in reproductive systems, overexpressed PD-MSCs could maximize the angiogenic effects in an ovarian tissues injured of rat model with partial ovariectomy and their therapeutic mechanism by enhanced vascular function via PDGF signaling.
Methods PD-MSCsPRL-1 (PRL-1) were generated by nonviral AMAXA gene delivery system and analyzed the vascular remodeling and follicular development in ovary. One week after Sprague–Dawley (SD) rats ovariectomy, Naïve and PRL-1 was transplanted. The animals were sacrificed at 1, 3 and 5 weeks after transplantation and vascular remodeling and follicular development were analyzed. Also, human umbilical vein endothelial cells (HUVECs) and ovarian explantation culture were performed to prove the specific effects and mechanism of PRL-1.
Results Vascular structures in ovarian tissues (e.g., number of vessels, thickness and lumen area) showed changes in the Naïve and PRL-1-overexpressed PD-MSC (PRL-1) transplantation (Tx) groups compared to the nontransplantation (NTx) group. Especially, PRL-1 induce to increase the expression of platelet-derived growth factor (PDGF), which plays a role in vascular remodeling as well as follicular development, compared to the NTx. Also, the expression of genes related to pericyte and vascular permeability in arteries was significantly enhanced in the PRL-1 compared to the NTx (p < 0.05). PRL-1 enhanced the vascular formation and permeability of human umbilical vein endothelial cells (HUVECs) via activated the PDGF signaling pathway. Conclusions Our results show that PRL-1 restored ovarian function by enhanced vascular function via PDGF signaling pathway. These findings offer new insight into the effects of functionally enhanced stem cell therapy for reproductive systems and should provide new avenues to develop more efficient therapies in degenerative medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02772-9.
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Affiliation(s)
- Hyeri Park
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea
| | - Jin Seok
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea.,Research Institute of Placenta Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Jun Hyeong You
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea
| | - Jae Yeon Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea.,Research Institute of Placenta Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Ja-Yun Lim
- Department of Health and Environmental Science, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02481, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea. .,Research Institute of Placenta Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
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17
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Combination Therapy of Placenta-Derived Mesenchymal Stem Cells with WKYMVm Promotes Hepatic Function in a Rat Model with Hepatic Disease via Vascular Remodeling. Cells 2022; 11:cells11020232. [PMID: 35053347 PMCID: PMC8773666 DOI: 10.3390/cells11020232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/05/2022] [Accepted: 01/07/2022] [Indexed: 12/24/2022] Open
Abstract
Changes in the structure and function of blood vessels are important factors that play a primary role in regeneration of injured organs. WKYMVm has been reported as a therapeutic factor that promotes the migration and proliferation of angiogenic cells. Additionally, we previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) induce hepatic regeneration in hepatic failure via antifibrotic effects. Therefore, our objectives were to analyze the combination effect of PD-MSCs and WKYMVm in a rat model with bile duct ligation (BDL) and evaluate their therapeutic mechanism. To analyze the anti-fibrotic and angiogenic effects on liver regeneration, it was analyzed using ELISA, qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry. Collagen accumulation was significantly decreased in PD-MSCs with the WKYMVm combination (Tx+WK) group compared with the nontransplantation (NTx) and PD-MSC-transplanted (Tx) group (p < 0.05). Furthermore, the combination of PD-MSCs with WKYMVm significantly promoted hepatic function by increasing hepatocyte proliferation and albumin as well as angiogenesis by activated FPR2 signaling (p < 0.05). The combination therapy of PD-MSCs with WKYMVm could be an efficient treatment in hepatic diseases via vascular remodeling. Therefore, the combination therapy of PD-MSCs with WKYMVm could be a new therapeutic strategy in degenerative medicine.
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18
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Kim KH, Lee KA. Metabolic Rewiring by Human Placenta-Derived Mesenchymal Stem Cell Therapy Promotes Rejuvenation in Aged Female Rats. Int J Mol Sci 2022; 23:ijms23010566. [PMID: 35008991 PMCID: PMC8745533 DOI: 10.3390/ijms23010566] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/22/2021] [Accepted: 12/30/2021] [Indexed: 01/17/2023] Open
Abstract
Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced responses at the metabolite and protein levels and serum biomarker(s) of aging and/or rejuvenation. We observed weight loss after hPD-MSC therapy. Importantly, insulin-like growth factor-I (IGF-I), known prolongs healthy life spans, were markedly elevated in serum. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis identified 176 metabolites, among which the levels of 3-hydroxybutyric acid, glycocholic acid, and taurine, which are associated with health and longevity, were enhanced after hPD-MSC stimulation. Furthermore, after hPD-MSC therapy, the levels of vitamin B6 and its metabolite pyridoxal 5′-phosphate were markedly increased in the serum and liver, respectively. Interestingly, hPD-MSC therapy promoted serotonin production due to increased vitamin B6 metabolism rates. Increased liver serotonin levels after multiple-injection therapy altered the expression of mRNAs and proteins associated with hepatocyte proliferation and mitochondrial biogenesis. Changes in metabolites in circulation after hPD-MSC therapy can be used to identify biomarker(s) of aging and/or rejuvenation. In addition, serotonin is a valuable therapeutic target for reversing aging-associated liver degeneration.
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19
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Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells Int 2021; 2021:5513309. [PMID: 34824587 PMCID: PMC8610645 DOI: 10.1155/2021/5513309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a severe health problem that endangers human health worldwide. Mesenchymal stem cell (MSC) therapy is a novel treatment for patients with different liver diseases due to its vast expansion potential and distinctive immunomodulatory properties. Despite several preclinical trials having confirmed the considerable efficacy of MSC therapy in liver diseases, the questionable safety and efficacy still limit its application. As a precursor cell, MSCs can adjust their characteristics in response to the surrounding microenvironment. The microenvironment provides physical and chemical factors essential for stem cell survival, proliferation, and differentiation. However, the mechanisms are still not completely understood. We, therefore, summarized the mechanisms underlying the MSC immune response, especially the interaction between MSCs and the liver microenvironment, discussing how to achieve better therapeutic effects.
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20
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Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium. Stem Cell Res Ther 2021; 12:551. [PMID: 34689832 PMCID: PMC8543968 DOI: 10.1186/s13287-021-02616-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Background Cholesterol accumulation and calcium depletion induce hepatic injury via the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. We previously reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCsPRL−1) promoted liver regeneration via mitochondrial dynamics in a cirrhotic rat model. However, the role of PRL-1 in ER stress-dependent calcium is not clear. Therefore, we demonstrated that PD-MSCsPRL−1 improved hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL). Methods Liver cirrhosis was induced in Sprague–Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCsPRL−1 (2 × 106 cells) were intravenously administered to animals, and their therapeutic effects were analyzed. WB-F344 cells exposed to thapsigargin (TG) were cocultured with PD-MSCs or PD-MSCsPRL−1. Results ER stress markers, e.g., eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were increased in the nontransplantation group (NTx) compared to the control group. PD-MSCsPRL−1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers, e.g., sarco/endoplasmic reticulum Ca2+ -ATPase 2b (SERCA2b), inositol 1,4,5-trisphosphate receptor (IP3R), mitochondrial calcium uniporter (MCU), and voltage-dependent anion channel 1 (VDAC1) (*p < 0.05). Cocultivation of TG-treated WB-F344 cells with PD-MSCsPRL−1 decreased cytosolic calmodulin (CaM) expression and cytosolic and mitochondrial Ca2+ concentrations. However, the ER Ca2+ concentration was increased compared to PD-MSCs (*p < 0.05). PRL-1 activated phosphatidylinositol-3-kinase (PI3K) signaling via epidermal growth factor receptor (EGFR), which resulted in calcium increase via CaM expression. Conclusions These findings suggest that PD-MSCsPRL−1 improved hepatic functions via calcium changes and attenuated ER stress in a BDL-injured rat model. Therefore, these results provide useful data for the development of next-generation MSC-based stem cell therapy for regenerative medicine in chronic liver disease. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02616-y.
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21
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Choi JH, Park S, Kim GD, Kim JY, Jun JH, Bae SH, Baik SK, Hwang SG, Kim GJ. Increased Phosphatase of Regenerating Liver-1 by Placental Stem Cells Promotes Hepatic Regeneration in a Bile-Duct-Ligated Rat Model. Cells 2021; 10:cells10102530. [PMID: 34685509 PMCID: PMC8533985 DOI: 10.3390/cells10102530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 11/16/2022] Open
Abstract
Phosphatase of regenerating liver-1 (PRL-1) controls various cellular processes and liver regeneration. However, the roles of PRL-1 in liver regeneration induced by chorionic-plate-derived mesenchymal stem cells (CP-MSCs) transplantation remain unknown. Here, we found that increased PRL-1 expression by CP-MSC transplantation enhanced liver regeneration in a bile duct ligation (BDL) rat model by promoting the migration and proliferation of hepatocytes. Engrafted CP-MSCs promoted liver function via enhanced hepatocyte proliferation through increased PRL-1 expression in vivo and in vitro. Moreover, higher increased expression of PRL-1 regulated CP-MSC migration into BDL-injured rat liver through enhancement of migration-related signals by increasing Rho family proteins. The dual effects of PRL-1 on proliferation of hepatocytes and migration of CP-MSCs were substantially reduced when PRL-1 was silenced with siRNA-PRL-1 treatment. These findings suggest that PRL-1 may serve as a multifunctional enhancer for therapeutic applications of CP-MSC transplantation.
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Affiliation(s)
- Jong Ho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung-si 25457, Korea;
| | - Sohae Park
- Department of Biomedical Science, CHA University, Seongnam-si 13488, Korea; (S.P.); (J.Y.K.); (J.H.J.)
- Research Institute of Placental Science, CHA University, Seongnam-si 13488, Korea
| | - Gi Dae Kim
- Department of Food and Nutrition, Kyungnam University, Changwon-si 51767, Korea;
| | - Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam-si 13488, Korea; (S.P.); (J.Y.K.); (J.H.J.)
| | - Ji Hye Jun
- Department of Biomedical Science, CHA University, Seongnam-si 13488, Korea; (S.P.); (J.Y.K.); (J.H.J.)
- Research Institute of Placental Science, CHA University, Seongnam-si 13488, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Catholic University Medical College, Seoul 03312, Korea;
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Seong-Gyu Hwang
- CHA Bundang Medical Center, Department of Internal Medicine, Division of Gastroenterology, CHA University School of Medicine, Seongnam-si 13496, Korea;
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam-si 13488, Korea; (S.P.); (J.Y.K.); (J.H.J.)
- Research Institute of Placental Science, CHA University, Seongnam-si 13488, Korea
- Correspondence: ; Tel.: +82-31-881-7145
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22
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Park JM, Han YM, Hahm KB. Rejuvenation of Helicobacter pylori-Associated Atrophic Gastritis Through Concerted Actions of Placenta-Derived Mesenchymal Stem Cells Prevented Gastric Cancer. Front Pharmacol 2021; 12:675443. [PMID: 34483897 PMCID: PMC8416416 DOI: 10.3389/fphar.2021.675443] [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: 03/03/2021] [Accepted: 06/22/2021] [Indexed: 01/06/2023] Open
Abstract
Chronic Helicobacter pylori infection causes gastric cancer via the progression of precancerous chronic atrophic gastritis (CAG). Therefore, repairing gastric atrophy could be a useful strategy in preventing H. pylori-associated gastric carcinogenesis. Although eradication of the bacterial pathogen offers one solution to this association, this study was designed to evaluate an alternative approach using mesenchymal stem cells to treat CAG and prevent carcinogenesis. Here, we used human placenta-derived mesenchymal stem cells (PD-MSCs) and their conditioned medium (CM) to treat H. pylori-associated CAG in a mice/cell model to explore their therapeutic effects and elucidate their molecular mechanisms. We compared the changes in the fecal microbiomes in response to PD-MSC treatments, and chronic H. pylori-infected mice were given ten treatments with PD-MSCs before being sacrificed for end point assays at around 36 weeks of age. These animals presented with significant reductions in the mean body weights of the control group, which were eradicated following PD-MSC treatment (p < 0.01). Significant changes in various pathological parameters including inflammation, gastric atrophy, erosions/ulcers, and dysplastic changes were noted in the control group (p < 0.01), but these were all significantly reduced in the PD-MSC/CM-treated groups. Lgr5+, Ki-67, H+/K+-ATPase, and Musashi-1 expressions were all significantly increased in the treated animals, while inflammatory mediators, MMP, and apoptotic executors were significantly decreased in the PD-MSC group compared to the control group (p < 0.001). Our model showed that H. pylori-initiated, high-salt diet-promoted gastric atrophic gastritis resulted in significant changes in the fecal microbiome at the phylum/genus level and that PD-MSC/CM interventions facilitated a return to more normal microbial communities. In conclusion, administration of PD-MSCs or their conditioned medium may present a novel rejuvenating agent in preventing the progression of H. pylori-associated premalignant lesions.
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Affiliation(s)
- Jong Min Park
- College of Oriental Medicine, Daejeon University, Daejeon, Korea
| | - Young Min Han
- Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Ki Baik Hahm
- Medpacto Research Institute, Medpacto, Seoul, Korea.,CHA Cancer Preventive Research Center, CHA Bio Complex, Seongnam, Korea
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23
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Park M, Kim JY, Kang JM, Lee HJ, Banga JP, Kim GJ, Lew H. PRL-1 overexpressed placenta-derived mesenchymal stem cells suppress adipogenesis in Graves' ophthalmopathy through SREBP2/HMGCR pathway. Stem Cell Res Ther 2021; 12:304. [PMID: 34051850 PMCID: PMC8164285 DOI: 10.1186/s13287-021-02337-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/18/2021] [Indexed: 11/25/2022] Open
Abstract
Background Graves’ ophthalmopathy (GO) is a disorder, in which orbital connective tissues get in inflammation and increase in volume. Stimulants such as thyroid-stimulating hormone (TSH), insulin-like growth factor 1(IGF-1), IL-1, interferon γ, and platelet-derived growth factor cause differentiation into adipocytes of orbital fibroblasts (OFs) in the orbital fat and extraocular muscles. Human placental mesenchymal stem cells (hPMSCs) are known to have immune modulation effects on disease pathogenesis. Some reports suggest that hPMSCs can elicit therapeutic effects, but to date, research on this has been insufficient. In this study, we constructed PRL-1 overexpressed hPMSCs (hPMSCsPRL-1) in an attempt to enhance the suppressive function of adipogenesis in GO animal models. Methods In order to investigate the anti-adipogenic effects, primary OFs were incubated with differentiation medium for 10 days. After co-culturing with hPMSCsPRL-1, the characteristics of the OFs were analyzed using Nile red stain and quantitative real-time polymerase chain reaction. We then examined the in vivo regulatory effectiveness of hPMSCsPRL-1 in a GO mouse model that immunized by leg muscle electroporation of pTriEx1.1Neo-hTSHR A-subunit plasmid. Human PMSCsPRL-1 injection was performed in left orbit. We also analyzed the anti-adipogenic effects of hPMSCsPRL-1 in the GO model. Results We found that hPMSCsPRL-1 inhibited adipogenic activation factors, specifically PPARγ, C/EBPα, FABP4, SREBP2, and HMGCR, by 75.1%, 50%, 79.6%, 81.8%, and 87%, respectively, compared with naïve hPMSCs in adipogenesis-induced primary OFs from GO. Moreover, hPMSCsPRL-1 more effectively inhibited adipogenic factors ADIPONECTIN and HMGCR by 53.2% and 31.7%, respectively, than hPMSCs, compared with 15.8% and 29.8% using steroids in the orbital fat of the GO animal model. Conclusion Our findings suggest that hPMSCsPRL-1 would restore inflammation and adipogenesis of GO model and demonstrate that they could be applied as a novel treatment for GO patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02337-2.
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Affiliation(s)
- Mira Park
- Department of Ophthalmology, Bundang CHA Medical Center, CHA University, Seongnam, Gyeonggi-do, 13496, Republic of Korea
| | - Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea.,Research Institute of Placental Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Jun Mo Kang
- CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Hey Jin Lee
- CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | | | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea.
| | - Helen Lew
- Department of Ophthalmology, Bundang CHA Medical Center, CHA University, Seongnam, Gyeonggi-do, 13496, Republic of Korea.
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Gorodetsky R, Aicher WK. Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies. Int J Mol Sci 2021; 22:5302. [PMID: 34069909 PMCID: PMC8157571 DOI: 10.3390/ijms22105302] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.
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Affiliation(s)
- Raphael Gorodetsky
- Biotechnology and Radiobiology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Wilhelm K. Aicher
- Center of Medical Research, Department of Urology at UKT, Eberhard-Karls-University, 72076 Tuebingen, Germany
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25
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Cho J, Kim TH, Seok J, Jun JH, Park H, Kweon M, Lim JY, Kim GJ. Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway. J Transl Med 2021; 101:304-317. [PMID: 33303971 PMCID: PMC7892345 DOI: 10.1038/s41374-020-00513-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/06/2020] [Accepted: 11/06/2020] [Indexed: 12/22/2022] Open
Abstract
Angiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 105) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.
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Affiliation(s)
- Jinki Cho
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Tae-Hee Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine Hospital, Bucheon, Gyunggi-do, 14584, Republic of Korea
| | - Jin Seok
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Ji Hye Jun
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Hyeri Park
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Minyeoung Kweon
- College of Life Science, University of Glasgow, Glasgow, Scotland, G12 8QQ, UK
| | - Ja-Yun Lim
- Department of Health and Environmental Science, Korea University, Seoul, 02481, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea.
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26
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Kim JY, Choi JH, Kim SH, Park H, Lee D, Kim GJ. Efficacy of Gene Modification in Placenta-Derived Mesenchymal Stem Cells Based on Nonviral Electroporation. Int J Stem Cells 2021; 14:112-118. [PMID: 33377456 PMCID: PMC7904523 DOI: 10.15283/ijsc20117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/28/2020] [Accepted: 10/28/2020] [Indexed: 01/20/2023] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy using gene delivery systems has been suggested for degenerative diseases. Although MSC-based clinical applications are effective and safe, the mode of action remains unclear. Researchers have commonly applied viral-based gene modification because this system has efficient vehicles. While viral transfection carries many risks, such as oncogenes and chromosomal integration, nonviral gene delivery techniques are less expensive, easier to handle, and safe, although they are less efficient. The electroporation method, which uses Nucleofection technology, provides critical opportunities for hard-to-transfect primary cell lines, including MSCs. Therefore, to improve the therapeutic efficacy using genetically modified MSCs, researchers must determine the optimal conditions for the introduction of the Nucleofection technique in MSCs. Here, we suggest optimal methods for gene modification in PD-MSCs using an electroporation gene delivery system for clinical application.
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Affiliation(s)
- Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam, Korea
| | - Jong Ho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Se Ho Kim
- Department of Biomedical Science, CHA University, Seongnam, Korea
| | - Hyeri Park
- Department of Biomedical Science, CHA University, Seongnam, Korea
| | - Dongsook Lee
- Hamchoon Women's clinic, Research Center of Fertility & Genetics, Seoul, Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Korea
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Seok J, Jun S, Cho J, Park S, Lee JO, Kim GJ. Human placenta-derived mesenchymal stem cells induce trophoblast invasion via dynamic effects on mitochondrial function. J Cell Physiol 2021; 236:6678-6690. [PMID: 33624308 PMCID: PMC9135125 DOI: 10.1002/jcp.30330] [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: 03/05/2020] [Revised: 02/01/2021] [Accepted: 02/04/2021] [Indexed: 12/19/2022]
Abstract
The trophoblast is a critical cell for placental development and embryo implantation in the placenta. We previously reported that placenta‐derived mesenchymal stem cells (PD‐MSCs) increase trophoblast invasion through several signaling pathways. However, the paracrine effects of PD‐MSCs on mitochondrial function in trophoblasts are still unclear. Therefore, the objective of the study was to analyze the mitochondrial function of trophoblasts in response to cocultivation with PD‐MSCs. The results showed that PD‐MSCs regulate the balance between cell survival and death and protect damaged mitochondria in trophoblasts from oxidative stress. Moreover, PD‐MSCs upregulate factors involved in mitochondrial autophagy in trophoblast cells. Finally, PD‐MSCs improve trophoblast invasion. Taken together, the data indicate that PD‐MSCs can regulate trophoblast invasion through dynamic effects on mitochondrial energy metabolism. These results support the fundamental role of mitochondrial energy mechanism in trophoblast invasion and suggest a new therapeutic strategy for infertility.
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Affiliation(s)
- Jin Seok
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Sujin Jun
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jinki Cho
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Sohea Park
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
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28
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Cargnoni A, Papait A, Masserdotti A, Pasotti A, Stefani FR, Silini AR, Parolini O. Extracellular Vesicles From Perinatal Cells for Anti-inflammatory Therapy. Front Bioeng Biotechnol 2021; 9:637737. [PMID: 33614619 PMCID: PMC7892960 DOI: 10.3389/fbioe.2021.637737] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/19/2021] [Indexed: 01/08/2023] Open
Abstract
Perinatal cells, including cells from placenta, fetal annexes (amniotic and chorionic membranes), umbilical cord, and amniotic fluid display intrinsic immunological properties which very likely contribute to the development and growth of a semiallogeneic fetus during pregnancy. Many studies have shown that perinatal cells can inhibit the activation and modulate the functions of various inflammatory cells of the innate and adaptive immune systems, including macrophages, neutrophils, natural killer cells, dendritic cells, and T and B lymphocytes. These immunological properties, along with their easy availability and lack of ethical concerns, make perinatal cells very useful/promising in regenerative medicine. In recent years, extracellular vesicles (EVs) have gained great interest as a new therapeutic tool in regenerative medicine being a cell-free product potentially capable, thanks to the growth factors, miRNA and other bioactive molecules they convey, of modulating the inflammatory microenvironment thus favoring tissue regeneration. The immunomodulatory actions of perinatal cells have been suggested to be mediated by still not fully identified factors (secretoma) secreted either as soluble proteins/cytokines or entrapped in EVs. In this review, we will discuss how perinatal derived EVs may contribute toward the modulation of the immune response in various inflammatory pathologies (acute and chronic) by directly targeting different elements of the inflammatory microenvironment, ultimately leading to the repair and regeneration of damaged tissues.
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Affiliation(s)
- Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alice Masserdotti
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Pasotti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
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Xie F, Teng L, Xu J, Lu J, Zhang C, Yang L, Ma X, Zhao M. Adipose-derived mesenchymal stem cells inhibit cell proliferation and migration and suppress extracellular matrix synthesis in hypertrophic-scar and keloid fibroblasts. Exp Ther Med 2021; 21:139. [PMID: 33456506 PMCID: PMC7791925 DOI: 10.3892/etm.2020.9571] [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] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/26/2020] [Indexed: 12/13/2022] Open
Abstract
Pathological scars occur during skin wound healing, and the use of adipose-derived stem cells (ADSCs) is one of the various treatments. The present study aimed to investigate the in vitro effects of ADSCs on the biological properties of hypertrophic scar fibroblasts (HSFs) and keloid fibroblasts (KFs), such as proliferation, migration, and the synthesis of extracellular matrix proteins. Transwell chambers were used to establish a co-culture system of ADSCs with normal skin fibroblasts (NFs), HSFs or KFs. The effect of ADSCs on the proliferation of fibroblasts was evaluated by CCK8 measurement, while the migration ability of fibroblasts was assessed using cell scratch assay. The expression of extracellular matrix proteins was measured by immunoblotting. Co-culture of NFs with ADSCs did not affect cell proliferation and migration, nor the expression of extracellular matrix proteins [collagen-I, collagen-III, fibronectin (FN) and α-smooth muscle actin (α-SMA)] in NFs. However, as with the inhibitor SB431542, ADSCs significantly inhibited cell proliferation and migration and the expression of extracellular matrix proteins (collagen-I, collagen-III, FN and α-SMA), but also suppressed the protein expression of transforming growth factor β1 (TGF-β1), phosphorylated (p-) mothers against decapentaplegic homolog (Smad) 2, p-Smad3 and Smad7 in HSFs and KFs. The results show that ADSCs inhibited cell proliferation and migration and the expression of extracellular matrix proteins in HSCs and KFs in vitro, possibly through inhibition of the TGF-β1/Smad pathway.
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Affiliation(s)
- Fang Xie
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Li Teng
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Jiajie Xu
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Jianjian Lu
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Chao Zhang
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Liya Yang
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Xiaoyang Ma
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Minghao Zhao
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
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30
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Zhou Q, Fan L, Li J. Liver Regeneration and Tissue Engineering. ARTIFICIAL LIVER 2021:73-94. [DOI: 10.1007/978-981-15-5984-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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31
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de la Torre P, Flores AI. Current Status and Future Prospects of Perinatal Stem Cells. Genes (Basel) 2020; 12:6. [PMID: 33374593 PMCID: PMC7822425 DOI: 10.3390/genes12010006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023] Open
Abstract
The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.
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Affiliation(s)
| | - Ana I. Flores
- Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Avda. Cordoba s/n, 28041 Madrid, Spain;
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Kim JY, Choi JH, Jun JH, Park S, Jung J, Bae SH, Kim GJ. Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model. Stem Cell Res Ther 2020; 11:512. [PMID: 33246509 PMCID: PMC7694436 DOI: 10.1186/s13287-020-02029-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as an alternative cell therapy agent that has become a next-generation stem cell treatment. Phosphatase of regenerating liver-1 (PRL-1), an immediate early gene, plays a critical role during liver regeneration. Here, we generated enhanced PRL-1 in PD-MSCs (PD-MSCsPRL-1, PRL-1+) using lentiviral and nonviral gene delivery systems and investigated mitochondrial functions by PD-MSCPRL-1 transplantation for hepatic functions in a rat bile duct ligation (BDL) model. METHODS PD-MSCsPRL-1 were generated by lentiviral and nonviral AMAXA gene delivery systems and analyzed for their characteristics and mitochondrial metabolic functions. Liver cirrhosis was induced in Sprague-Dawley (SD) rats using common BDL for 10 days. PKH67+ naïve and PD-MSCsPRL-1 using a nonviral sysyem (2 × 106 cells/animal) were intravenously administered into cirrhotic rats. The animals were sacrificed at 1, 2, 3, and 5 weeks after transplantation and engraftment of stem cells, and histopathological analysis and hepatic mitochondrial functions were performed. RESULTS PD-MSCsPRL-1 were successfully generated using lentiviral and nonviral AMAXA systems and maintained characteristics similar to those of naïve cells. Compared with naïve cells, PD-MSCsPRL-1 improved respirational metabolic states of mitochondria. In particular, mitochondria in PD-MSCsPRL-1 generated by the nonviral AMAXA system showed a significant increase in the respirational metabolic state, including ATP production and mitochondrial biogenesis (*p < 0.05). Furthermore, transplantation of PD-MSCsPRL-1 using a nonviral AMAXA system promoted engraftment into injured target liver tissues of a rat BDL cirrhotic model and enhanced the metabolism of mitochondria via increased mtDNA and ATP production, thereby improving therapeutic efficacy. CONCLUSIONS Our findings will further our understanding of the therapeutic mechanism of enhanced MSCs and provide useful data for the development of next-generation MSC-based cell therapy and therapeutic strategies for regenerative medicine in liver disease.
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Affiliation(s)
- Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Jong Ho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung, 25457, Republic of Korea
| | - Ji Hye Jun
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Sohae Park
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Jieun Jung
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Catholic University Medical College, Seoul, 06591, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea.
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Peng SY, Wu TH, Lin TY, Hii LY, Chan KS, Fu TY, Chang SC, Shen PC, Liu KY, Shaw SW. Application of cattle placental stem cells for treating ovarian follicular cyst. World J Stem Cells 2020; 12:1366-1376. [PMID: 33312404 PMCID: PMC7705470 DOI: 10.4252/wjsc.v12.i11.1366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/02/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High humidity and temperature in Taiwan have significant effects on the reproductivity of Holstein cattle, resulting in the occurrence of bovine ovarian follicular cyst (OFC). Because of economic loss from OFC, manual rupture and hormone injection have been advocated for the management of OFC. However, these incomplete treatments increase hormone resistance in cattle. Mesenchymal stem cells (MSCs) derived from placental stem cells (PSCs) demonstrate potential properties for the treatment of several diseases via promoting angiogenesis and immune modulation. AIM To establish the possibility of cattle placental stem cells (CPSCs) as a treatment modality for OFC of cows in Taiwan. METHODS The cows with OFC were divided into three groups: control (BC1 and BC2), hormone (H1 and H2), and CPSC (PS1 and PS2) treatment groups. In the hormone treatment group, the cows were given gonadotrophin-releasing hormone (GnRH)-prostaglandin-GnRH intramuscular injection with or without drainage of follicular fluid. In the CPSC treatment group, CPSCs were isolated from the placenta after labor. With the identification of surface antigen on stem cells, the cows were administered ovarian injection of 1 × 106 or 6 × 106 CPSCs with drainage. In all groups, OFC was scanned by ultrasound once a week for a total of seven times. The concentrations of estradiol and progesterone in serum were tested in the same period. The estrus cycle was analyzed by food intake and activity. If estrus was detected, artificial insemination was conducted. Then the cow was monitored by ultrasound for confirmation of pregnancy. RESULTS After 7 d of culture, CPSCs were successfully isolated from placental pieces. CPSCs significantly proliferated every 24 h and had high expression of MSC markers such as cluster of differentiation 44, as determined by flow cytometry. Ultrasound showed lower numbers of OFCs with drainage of follicular fluid. We achieved recovery rates of 0%, 50%, 50%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. Higher concentrations of progesterone were detected in the CPSC treatment groups. However, both hormone and CPSC treatment groups had no significant difference in the concentration of estradiol. The estrus rate was 0%, 100%, 25%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. The two fetuses were born in H2 and PS1. In brief, cows with CPSC injection achieved higher recovery, estrus, and inseminated conception rates. CONCLUSION CPSCs have efficacy in treating cows with OFC, and thus, may serve as an alternative treatment for reproductive disorders.
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Affiliation(s)
- Shao-Yu Peng
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tsung-Hsin Wu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tzu-Yi Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ling-Yien Hii
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Kok-Seong Chan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Tzu-Yen Fu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Shen-Chang Chang
- Kaohsiung Animal Propagation Station, Livestock Research Institute, Council of Agriculture, Executive Yuan, Pingtung 912, Taiwan
| | - Perng-Chih Shen
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Kang-You Liu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Steven W. Shaw
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
- Prenatal Cell and Gene Therapy Group, Institute for Women's Health, University College London, London WC1E 6HU, United Kingdom.
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Choi JH, Seok J, Lim SM, Kim TH, Kim GJ. Microenvironmental changes induced by placenta-derived mesenchymal stem cells restore ovarian function in ovariectomized rats via activation of the PI3K-FOXO3 pathway. Stem Cell Res Ther 2020; 11:486. [PMID: 33198818 PMCID: PMC7667861 DOI: 10.1186/s13287-020-02002-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/29/2020] [Indexed: 12/23/2022] Open
Abstract
Background Translational studies have explored the therapeutic potential and feasibility of mesenchymal stem cells (MSCs) in several degenerative diseases; however, mechanistic studies of the function of these cells have been insufficient. As ovarian failure causes anovulation as well as ovarian steroid hormonal imbalances, the specific aims of this study were to analyze the therapeutic role of placenta-derived MSCs (PD-MSCs) in an ovarian failure ovariectomy (OVX) rat model and evaluate whether PD-MSC transplantation (Tx) improved folliculogenesis and oocyte maturation in the injured ovary through PI3K/Akt and FOXO signaling. Methods Blood and ovary tissue were collected and analyzed after various PD-MSC Tx treatments in an ovariectomized rat model. Changes in the expression of folliculogenesis- and ovary regeneration-related genes induced by PD-MSC treatments were analyzed by qRT-PCR, Western blotting, and histological analysis. Results The levels of hormones related to ovary function were significantly increased in the PD-MSC Tx groups compared with those in the nontransplantation group (NTx). The follicle numbers in the ovarian tissues were increased along with the increased expression of genes related to folliculogenesis in the PD-MSC Tx groups compared with the NTx groups. Furthermore, Tx PD-MSCs induced follicle maturation by increasing the phosphorylation of GSK3 beta and FOXO3 (p < 0.05) and shifting the balance of growth and apoptosis in oocytes. Conclusions Taken together, these results show that PD-MSC Tx can restore ovarian function and induce ovarian folliculogenesis via the PI3K/Akt and FOXO signaling pathway.
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Affiliation(s)
- Jong Ho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung-si, 25457, Republic of Korea
| | - Jin Seok
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Seung Mook Lim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Tae Hee Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine Hospital, Asan, 14584, Gyoenggi-do, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
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Seok J, Jun S, Lee JO, Kim GJ. Mitochondrial Dynamics in Placenta-Derived Mesenchymal Stem Cells Regulate the Invasion Activity of Trophoblast. Int J Mol Sci 2020; 21:ijms21228599. [PMID: 33202697 PMCID: PMC7696686 DOI: 10.3390/ijms21228599] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/12/2020] [Indexed: 12/21/2022] Open
Abstract
Mitochondrial dynamics are involved in many cellular events, including the proliferation, differentiation, and invasion/migration of normal as well as cancerous cells. Human placenta-derived mesenchymal stem cells (PD-MSCs) were known to regulate the invasion activity of trophoblasts. However, the effects of PD-MSCs on mitochondrial function in trophoblasts are still insufficiently understood. Therefore, the objectives of this study are to analyze the factors related to mitochondrial function and investigate the correlation between trophoblast invasion and mitophagy via PD-MSC cocultivation. We assess invasion ability and mitochondrial function in invasive trophoblasts according to PD-MSC cocultivation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and extracellular flux (XF) assay. Under PD-MSCs co-cultivation, invasion activity of a trophoblast is increased via activation of the Rho signaling pathway as well as Matrix metalloproteinases (MMPs). Additionally, the expression of mitochondrial function (e.g., reactive oxygen species (ROS), calcium, and adenosine triphosphate (ATP) synthesis) in trophoblasts are increased via PD-MSCs co-cultivation. Finally, PD-MSCs regulate mitochondrial autophagy factors in invasive trophoblasts via regulating the balance between PTEN-induced putative kinase 1 (PINK1) and parkin RBR E3 ubiquitin protein ligase (PARKIN) expression. Taken together, these results demonstrate that PD-MSCs enhance the invasion ability of trophoblasts via altering mitochondrial dynamics. These results support the fundamental mechanism of trophoblast invasion via mitochondrial function and provide a new stem cell therapy for infertility.
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Affiliation(s)
- Jin Seok
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea; (J.S.); (S.J.)
| | - Sujin Jun
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea; (J.S.); (S.J.)
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea;
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea; (J.S.); (S.J.)
- Correspondence: ; Tel.: +82-31-881-7245
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Kim KH, Kim EY, Kim GJ, Ko JJ, Cha KY, Koong MK, Lee KA. Human placenta-derived mesenchymal stem cells stimulate ovarian function via miR-145 and bone morphogenetic protein signaling in aged rats. Stem Cell Res Ther 2020; 11:472. [PMID: 33153492 PMCID: PMC7643421 DOI: 10.1186/s13287-020-01988-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 10/20/2020] [Indexed: 11/25/2022] Open
Abstract
Background Aging has detrimental effects on the ovary, such as a progressive reduction in fertility and decreased hormone production, that greatly reduce the quality of life of women. Thus, the current study was undertaken to investigate whether human placenta-derived mesenchymal stem cell (hPD-MSC) treatment can restore the decreases in folliculogenesis and ovarian function that occur with aging. Methods Acclimatized 52-week-old female SD rats were randomly divided into four groups: single hPD-MSC (5 × 105) therapy, multiple (three times, 10-day intervals) hPD-MSC therapy, control (PBS), and non-treated groups. hPD-MSC therapy was conducted by tail vein injection into aged rats. The rats were sacrificed 1, 2, 3, and 5 weeks after the last injection. hPD-MSC tracking and follicle numbers were histologically confirmed. The serum levels of sex hormones and circulating miRNAs were detected by ELISA and qRT-PCR, respectively. TGF-β superfamily proteins and SMAD proteins in the ovary were detected by Western blot analysis. Results We observed that multiple transplantations of hPD-MSCs more effectively promoted primordial follicle activation and ovarian hormone (E2 and AMH) production than a single injection. After hPD-MSC therapy, the levels of miR-21-5p, miR-132-3p, and miR-212-3p, miRNAs associated with the ovarian reserve, were increased in the serum. Moreover, miRNAs (miR-16-5p, miR-34a-5p, and miR-191-5p) with known adverse effects on folliculogenesis were markedly suppressed. Importantly, the level of miR-145-5p was reduced after single- or multiple-injection hPD-MSC therapy, and we confirmed that miR-145-5p targets Bmpr2 but not Tgfbr2. Interestingly, downregulation of miR-145-5p led to an increase in BMPR2, and activation of SMAD signaling concurrently increased primordial follicle development and the number of primary and antral follicles. Conclusions Our study verified that multiple intravenous injections of hPD-MSCs led to improved ovarian function via miR-145-5p and BMP-SMAD signaling and proposed the future therapeutic potential of hPD-MSCs to promote ovarian function in women at advanced age to improve their quality of life during climacterium.
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Affiliation(s)
- Kyeoung-Hwa Kim
- Department of Biomedical Science, Institute of Reproductive Medicine, College of Life Science, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Eun-Young Kim
- Department of Biomedical Science, Institute of Reproductive Medicine, College of Life Science, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Gi Jin Kim
- Department of Biomedical Science, Institute of Reproductive Medicine, College of Life Science, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Jung-Jae Ko
- Department of Biomedical Science, Institute of Reproductive Medicine, College of Life Science, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Kwang Yul Cha
- CHA Stem Cell Institute, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Mi Kyung Koong
- CHA Fertility Center Seoul Station, CHA University School of Medicine, 416, Hangang-daero, Jung-gu, Seoul, 04637, South Korea
| | - Kyung-Ah Lee
- Department of Biomedical Science, Institute of Reproductive Medicine, College of Life Science, CHA University, Pangyo-Ro 335, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
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Kim JY, Park S, Lee HJ, Lew H, Kim GJ. Functionally enhanced placenta-derived mesenchymal stem cells inhibit adipogenesis in orbital fibroblasts with Graves' ophthalmopathy. Stem Cell Res Ther 2020; 11:469. [PMID: 33153489 PMCID: PMC7643360 DOI: 10.1186/s13287-020-01982-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Placenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties. Phosphatase of regenerating liver-1 (PRL-1) regulates the self-renewal ability of stem cells and promotes proliferation. Graves' ophthalmopathy (GO) is an autoimmune inflammatory disease of the orbit and is characterized by increased orbital levels of adipose tissue. Here, we evaluated the therapeutic mechanism for regulation of adipogenesis by PRL-1-overexpressing PD-MSCs (PD-MSCsPRL-1, PRL-1+) in orbital fibroblast (OF) with GO patients. METHODS PD-MSCs isolated from human placenta were transfected with the PRL-1 gene using nonviral transfection method. Primary OFs were isolated from orbital adipose tissue specimens from GO patients. After maturation as adipogenic differentiation, normal and GO-derived OFs were cocultured with naïve and PD-MSCsPRL-1. We analyzed the protein levels of adipogenesis markers and their signaling pathways in OFs from GO patients. RESULTS The characteristics of PD-MSCsPRL-1 were similar to those of naïve cells. OFs from GO patients induced adipocyte differentiation and had significantly decreased a lipid accumulation after coculture with PD-MSCsPRL-1 compared to naïve cells. The mRNA and protein expression of adipogenic markers was decreased in PD-MSCsPRL-1. Insulin-like growth factor-binding proteins (IGFBPs) secreting PD-MSCsPRL-1 downregulated the phosphorylated PI3K/AKT/mTOR expression in OFs from GO patients. Interestingly, IGFBP2, - 4, - 6, and - 7 expression in PD-MSCsPRL-1, which was mediated by integrin alpha 4 (ITGA4) and beta 7 (ITGB7), was higher than that in naïve cells and upregulated phosphorylated FAK downstream factor. CONCLUSION In summary, IGFBPs secreting PD-MSCPRL-1 inhibit adipogenesis in OFs from GO patients by upregulating phosphorylated FAK and downregulating PI3K/AKT/mTOR signaling pathway. The functional enhancement of PD-MSCs by nonviral gene modification provides a novel therapeutic strategy for the treatment of degenerative diseases.
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Affiliation(s)
- Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Sohae Park
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Hyun-Jung Lee
- Center for Non-Clinical Development, CHA Advanced Research Institute CHA University, Seongnam, 13488, Republic of Korea
| | - Helen Lew
- Department of Ophthalmology, CHA Bundang Medical Center CHA University, Seongnam, 13496, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea.
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Exosomes from Placenta-Derived Mesenchymal Stem Cells Are Involved in Liver Regeneration in Hepatic Failure Induced by Bile Duct Ligation. Stem Cells Int 2020; 2020:5485738. [PMID: 33133194 PMCID: PMC7568818 DOI: 10.1155/2020/5485738] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/17/2019] [Accepted: 11/26/2019] [Indexed: 12/16/2022] Open
Abstract
Although the liver has a regenerative capacity, hepatic failure is a severe and irreversible chronic disease. Placenta-derived mesenchymal stem cells (PD-MSCs) have distinctive features, such as recycling of the placenta waste after birth, ease of accessibility, abundant cell numbers, and strong immunosuppressive properties. Previously, we reported that PD-MSCs can regenerate the liver in hepatic failure through antifibrotic and autophagic mechanisms. Many reports have investigated whether exosomes, which are formed by the budding of vesicular bodies and are emitted into the blood, from stem cells have therapeutic potential in various diseases. C-reactive protein (CRP) is produced in hepatocytes and secreted via vessels. Therefore, the objectives of this study were to compare the expression of CRP in exosomes of a hepatic failure rat model (bile duct ligation, BDL) and to evaluate the therapeutic effect by their correlation between CRP and angiogenesis depending on PD-MSC transplantation. The exosomes were analyzed in a BDL rat model with transplantation of PD-MSCs through LC-MS analysis and precipitation solution. The exosomes, CRP, and factors related to these molecules were evaluated and quantified in exosomes as well as investigated by real-time PCR, Western blot, and immunofluorescence (IF) in vivo and in vitro. CRP was present in exosomes from serum of a rat model and increased by PD-MSC transplantation. In the exosomes, CRP upregulated the factors related to the Wnt signaling pathway and angiogenesis in the BDL rat liver-transplanted PD-MSCs. Also, CRP regulated the Wnt pathway and vascularization in rat hepatocytes by interacting with endothelial cells. Therefore, our findings indicate that CRP in exosomes excreted by PD-MSCs functions in angiogenesis via the Wnt signaling pathway.
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Placenta-Derived Mesenchymal Stem Cells Restore the Ovary Function in an Ovariectomized Rat Model via an Antioxidant Effect. Antioxidants (Basel) 2020; 9:antiox9070591. [PMID: 32640638 PMCID: PMC7402146 DOI: 10.3390/antiox9070591] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 12/18/2022] Open
Abstract
Oxidative stress is one of the major etiologies of ovarian dysfunction, including premature ovarian failure (POF). Previous reports have demonstrated the therapeutic effects of human placenta-derived mesenchymal stem cells (PD-MSCs) in an ovariectomized rat model (OVX). However, their therapeutic mechanism in oxidative stress has not been reported. Therefore, we investigated to profile the exosome of serum and demonstrate the therapeutic effect of PD-MSCs transplantation for the ovary function. We established an OVX model by ovariectomy and PD-MSCs transplantation was conducted by intravenous injection. Additionally, various factors in the exosome were profiled by LC-MS analysis. As a result, the transplanted PD-MSCs were engrafted into the ovary and the existence of antioxidant factors in the exosome. A decreased expression of oxidative stress markers and increased expression of antioxidant markers were shown in the transplantation (Tx) in comparison to the non-transplantation group (NTx) (* p < 0.05). The apoptosis factors were decreased, and ovary function was improved in Tx in comparison to NTx (* p < 0.05). These results suggest that transplanted PD-MSCs restore the ovarian function in an OVX model via upregulated antioxidant factors. These findings offer new insights for further understanding of stem cell therapy for reproductive systems.
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Feng Y, Wang L, Ma X, Yang X, Don O, Chen X, Qu J, Song Y. Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway. Stem Cell Res Ther 2020; 11:2. [PMID: 31900217 PMCID: PMC6942368 DOI: 10.1186/s13287-019-1492-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 10/31/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND ALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI. METHODS We examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, and FGF-10 with LPS via western blot and qRT-PCR. Western blot and chromatin immunoprecipitation assay detected the effects of liraglutide on GLP-1R, SPC, Ang-1, and FGF-10 through PKAc/β-catenin pathway and cAMP pathway. In the ALI animal model, we detected the effects of MSC and liraglutide combination on ALI symptoms by H&E staining, western blot, ELISA assays, calculating wet-to-dry ratio of the lung tissue, and counting neutrophils, leukocytes, and macrophages in mouse bronchoalveolar lavage fluid (BALF). RESULTS The data demonstrated that LPS reduced hCMSC proliferation and GLP-1R, SPC, Ang-1, and FGF-10 levels in a dose- and time-dependent manner. Liraglutide significantly dampened the reduction of GLP-1R, SPC, Ang-1, and FGF-10 and reversed the effect of LPS on hCMSCs, which could be regulated by GLP-1R and its downstream cAMP/PKAc/β-catenin-TCF4 signaling. Combination of hCMSCs with liraglutide showed more therapeutic efficacy than liraglutide alone in reducing LPS-induced ALI in the animal model. CONCLUSIONS These results reveal that the combination of hCMSCs and liraglutide might be an effective strategy for ALI treatment.
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Affiliation(s)
- Yun Feng
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 20003, China
- Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China
- Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China
| | - Linlin Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 20003, China
- Shanghai Respiratory Research Institute, Shanghai, 20003, China
| | - Xiaoying Ma
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Xiaotong Yang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Ocholi Don
- Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China
| | - Xiaoyan Chen
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China
| | - Jieming Qu
- Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China.
- Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 20025, China.
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 20003, China.
- Shanghai Respiratory Research Institute, Shanghai, 20003, China.
- Department of Pulmonary Medicine, Zhongshan Hospital, Qingpu Branch, Fudan University, Shanghai, 201700, China.
- National Clinical Research Center for Aging & Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Seok J, Jung HS, Park S, Lee JO, Kim CJ, Kim GJ. Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells. Stem Cell Res Ther 2020; 11:1. [PMID: 31900237 PMCID: PMC6941254 DOI: 10.1186/s13287-019-1471-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 10/10/2019] [Accepted: 10/25/2019] [Indexed: 02/08/2023] Open
Abstract
Background Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. Methods Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. Results Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. Conclusions These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.
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Affiliation(s)
- Jin Seok
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hyun Sook Jung
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Sohae Park
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea
| | - Chong Jai Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.
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Alterations in IL-6/STAT3 Signaling by Korean Mistletoe Lectin Regulate the Self-Renewal Activity of Placenta-Derived Mesenchymal Stem Cells. Nutrients 2019; 11:nu11112604. [PMID: 31671670 PMCID: PMC6893712 DOI: 10.3390/nu11112604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/19/2019] [Accepted: 10/25/2019] [Indexed: 12/13/2022] Open
Abstract
Korean mistletoe (Viscum album L. var. coloratum) lectin (VCA) is known as an anticancer drug. However, it is not clear whether VCA affects the self-renewal activity of mesenchymal stem cells (MSCs). Therefore, the objectives of this study were to analyze the effect of VCA on the proliferation of MSCs and expression of stemness markers. We also evaluated the usefulness of placenta-derived MSCs (PD-MSCs) as a screening tool. VCA was stably administered to MSCs, and analyzed self-renewal activities. The effect of IL-6 signaling on MSC proliferation was explored by quantitative methylation-specific PCR (qMSP) and western blot analysis. Compared with the control condition, low concentrations of VCA (10 pg/mL) induced an increase in the self-renewal activity of MSCs. Interestingly, a low concentration of VCA promoted IL-6 signaling in PD-MSCs through altered IL-6/STAT3 gene methylation. Furthermore, inhibition of IL-6 expression in PD-MSCs using an anti-IL-6 antibody caused a decrease in their self-renewal activity through IL-6/STAT3 signaling by altering IL-6/STAT3 gene methylation. These findings provide helpful data for understanding the mechanism of MSC self-renewal via VCA and show that VCA may be useful as a functional natural product for developing efficient therapies using placenta-derived stem cells.
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Choi YJ, Koo JB, Kim HY, Seo JW, Lee EJ, Kim WR, Cho JY, Hahm KB, Hong SP, Kim DH, Yoo JH. Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A. Stem Cell Res Ther 2019; 10:291. [PMID: 31547873 PMCID: PMC6757442 DOI: 10.1186/s13287-019-1385-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/14/2019] [Accepted: 08/15/2019] [Indexed: 12/22/2022] Open
Abstract
Background The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). Methods The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. Results UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. Conclusions UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis. Electronic supplementary material The online version of this article (10.1186/s13287-019-1385-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yoon Jeong Choi
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.,Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea
| | - Jun Bon Koo
- Clinical Research Center, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | | | - Jin Won Seo
- CHA Biotech, Co. Ltd., Seongnam, South Korea
| | | | - Woo Ram Kim
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Joo Young Cho
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Duk Hwan Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
| | - Jun-Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea. .,Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea.
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Sher N, Ofir R. Placenta-Derived Adherent Stromal Cell Therapy for Hematopoietic Disorders: A Case Study of PLX-R18. Cell Transplant 2019; 27:140-150. [PMID: 29562777 PMCID: PMC6434483 DOI: 10.1177/0963689717727543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The ephemeral placenta provides a noncontroversial source of young, healthy cells of both maternal and fetal origin from which cell therapy products can be manufactured. The 2 advantages of using live cells as therapeutic entities are: (a) in their environmental-responsive, multifactorial secretion profile and (b) in their activity as a “slow-release drug delivery system,” releasing secretions over a long time frame. A major difficulty in translating cell therapy to the clinic involves challenges of large-scale, robust manufacturing while maintaining product characteristics, identity, and efficacy. To address these concerns early on, Pluristem developed the PLacental eXpanded (PLX) platform, the first good manufacturing practice–approved, 3-dimensional bioreactor-based cell growth platform, to enable culture of mesenchymal-like adherent stromal cells harvested from the postpartum placenta. One of the products produced by Pluristem on this platform is PLX-R18, a product mainly comprising placental fetal cells, which is proven in vivo to alleviate radiation-induced lethality and to enhance hematopoietic cell counts after bone marrow (BM) failure. The identified mechanism of action of PLX-R18 cells is one of the cell-derived systemic pro-hematopoietic secretions, which upregulate endogenous secretions and subsequently rescue BM and peripheral blood cellularity, thereby boosting survival. PLX-R18 is therefore currently under study to treat both the hematopoietic syndrome of acute radiation (under the US Food and Drug Administration [FDA]’s Animal Rule) and the incomplete engraftment after BM transplantation (in a phase I study). In the future, they could potentially address additional hematological indications, such as aplastic anemia, myelodysplastic syndrome, primary graft failure, and acute or chronic graft versus host disease.
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Chai CY, Song J, Tan Z, Tai IC, Zhang C, Sun S. Adipose tissue-derived stem cells inhibit hypertrophic scar (HS) fibrosis via p38/MAPK pathway. J Cell Biochem 2019; 120:4057-4064. [PMID: 30260015 DOI: 10.1002/jcb.27689] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/27/2018] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The current study was designed to investigate the effects and underlying mechanisms of adipose tissue-derived stem cells (ADSCs) on hypertrophic scar (HS) fibrosis. METHOD Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot analysis were performed to detect the expression of collagen I (Col1), collagen III (Col3), and α-smooth muscle actin (α-SMA) after fibroblasts and cultured HS tissues were treated with ADSC medium. All data were analyzed by using SPSS17.0 software. Statistical analysis was performed by Student t tests. RESULTS The in vitro study showed that ADSC medium decreased the expression of Col1, Col3, and α-SMA. In addition, the protein level of p-p38 was downregulated by ADSC medium treatment in a concentration dependent manner. CONCLUSION The current study demonstrated that ADSC could decrease collagen deposition and scar formation in in vitro experiments. The regulation of the p38/MAPK signaling pathway might play an important role in the process.
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Affiliation(s)
- Chi-Yung Chai
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Junlong Song
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenwei Tan
- Department of Orthopedic Sursery, West China Hospital, Chengdu, Sichuan, China
| | - I-Chun Tai
- Southern Medical Science Ltd, Kaohsiung, Taiwan ROC
| | - Chaoying Zhang
- School of Basic Medical Sciences of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Qu C, Bao Z, Zhang X, Wang Z, Ren J, Zhou Z, Tian M, Cheng X, Chen X, Feng C. A thermosensitive RGD-modified hydroxybutyl chitosan hydrogel as a 3D scaffold for BMSCs culture on keloid treatment. Int J Biol Macromol 2019; 125:78-86. [DOI: 10.1016/j.ijbiomac.2018.12.058] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 11/29/2018] [Accepted: 12/04/2018] [Indexed: 11/30/2022]
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Kim SH, Jung J, Cho KJ, Choi JH, Lee HS, Kim GJ, Lee SG. Immunomodulatory Effects of Placenta-derived Mesenchymal Stem Cells on T Cells by Regulation of FoxP3 Expression. Int J Stem Cells 2018; 11:196-204. [PMID: 30343549 PMCID: PMC6285290 DOI: 10.15283/ijsc18031] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/23/2018] [Accepted: 07/31/2018] [Indexed: 12/17/2022] Open
Abstract
The immunomodulatory effects of mesenchymal stem cells (MSCs) are an important mediator of their therapeutic effects in stem cell therapy and regenerative medicine. The regulation mechanism of MSCs is orchestrated by several factors in both intrinsic and extrinsic events. Recent studies have shown that the dynamic expression of cytokines secreted from MSCs control T cell function and maturation by regulating the expression of FoxP3, which figures prominently in T cell differentiation. However, there is no evidence that placenta-derived mesenchymal stem cells (PD-MSCs) have strong immunomodulatory effects on T cell function and maturation via FoxP3 expression. Therefore, we compared the expression of FoxP3 in activated T cells isolated from peripheral blood and co-cultured with PD-MSCs or bone marrow-derived mesenchymal stem cells (BM-MSCs) and analyzed their effect on T cell proliferation and cytokine profiles. Additionally, we verified the immunomodulatory function of PD-MSCs by siRNA-mediated silencing of FoxP3. MSCs, including PD-MSCs and BM-MSCs, promoted differentiation of naive peripheral blood T cells into CD4+CD25+FoxP3+ regulatory T (Treg) cells. Intriguingly, the population of CD4+CD25+FoxP3+ Treg cells co-cultured with PD-MSCs was significantly expanded in comparison to those co-cultured with BM-MSCs or WI38 cells (p＜0.05, p＜0.001). Dynamic expression patterns of several cytokines, including anti- and pro-inflammatory cytokines and members of the transforming growth factor-beta (TGF-β) family secreted from PD-MSCs according to FoxP3 expression were observed. The results suggest that PD-MSCs have an immunomodulatory effect on T cells by regulating FoxP3 expression.
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Affiliation(s)
- Soo-Hwan Kim
- Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul,
Korea
- Department of Biomedical Laboratory Science, Gimcheon University, Gimcheon,
Korea
| | - Jieun Jung
- Placenta Research Laboratory, Department of Biomedical Science, CHA University, Seongnam,
Korea
| | - Kyung Jin Cho
- Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul,
Korea
- Faculty of Health and Environmental Science, College of Health Science, Korea University, Seoul,
Korea
| | - Jong-Ho Choi
- Placenta Research Laboratory, Department of Biomedical Science, CHA University, Seongnam,
Korea
| | - Hyeong Seon Lee
- Department of Biomedical Laboratory Science, Jungwon University, Goesan,
Korea
| | - Gi Jin Kim
- Placenta Research Laboratory, Department of Biomedical Science, CHA University, Seongnam,
Korea
| | - Seung Gwan Lee
- Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul,
Korea
- Faculty of Health and Environmental Science, College of Health Science, Korea University, Seoul,
Korea
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Han B, Fan J, Liu L, Tian J, Gan C, Yang Z, Jiao H, Zhang T, Liu Z, Zhang H. Adipose-derived mesenchymal stem cells treatments for fibroblasts of fibrotic scar via downregulating TGF-β1 and Notch-1 expression enhanced by photobiomodulation therapy. Lasers Med Sci 2018; 34:1-10. [DOI: 10.1007/s10103-018-2567-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 06/14/2018] [Indexed: 12/23/2022]
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Kim TH, Choi JH, Jun Y, Lim SM, Park S, Paek JY, Lee SH, Hwang JY, Kim GJ. 3D-cultured human placenta-derived mesenchymal stem cell spheroids enhance ovary function by inducing folliculogenesis. Sci Rep 2018; 8:15313. [PMID: 30333505 PMCID: PMC6193033 DOI: 10.1038/s41598-018-33575-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 09/18/2018] [Indexed: 12/18/2022] Open
Abstract
Placenta-derived mesenchymal stem cells (PD-MSCs) have numerous advantages over other adult MSCs that make them an attractive cell source for regenerative medicine. Here, we demonstrate the therapeutic effect of PD-MSCs in ovariectomized (Ovx) rats and compare their efficacy when generated via a conventional monolayer culture system (2D, naïve) and a spheroid culture system (3D, spheroid). PD-MSC transplantation significantly increased the estradiol level in Ovx rats compared with the non-transplantation (NTx) group. In particular, the estradiol level in the Spheroid group was significantly higher than that in the Naïve group at 2 weeks. Spheroid PD-MSCs exhibited a significantly higher efficiency of engraftment onto ovarian tissues at 2 weeks. The mRNA and protein expression levels of Nanos3, Nobox, and Lhx8 were also significantly increased in the Spheroid group compared with those in the NTx group at 1 and 2 weeks. These results suggest that PD-MSC transplantation can restore ovarian function in Ovx rats by increasing estrogen production and enhancing folliculogenesis-related gene expression levels and further indicate that spheroid-cultured PD-MSCs have enhanced therapeutic potential via increased engraftment efficiency. These findings improve our understanding of stem-cell-based therapies for reproductive systems and may suggest new avenues for developing efficient therapies using 3D cultivation systems.
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Affiliation(s)
- Tae-Hee Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine Hospital, 170 Jomaru-ro, Wonmi-gu, Bucheon-si, Gyunggi-do, Republic of Korea
| | - Jong Ho Choi
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyunggi-do, Republic of Korea
| | - Yesl Jun
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, Republic of Korea
| | - Seung Mook Lim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyunggi-do, Republic of Korea
| | - Sohae Park
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyunggi-do, Republic of Korea
| | - Jin-Young Paek
- Department of Clinical Pathology, CHA Gangnam Medical Center, CHA University, School of Medicine, 566 Nonhyun-ro, Gangnam-gu, Seoul, Republic of Korea
| | - Sang-Hoon Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, Republic of Korea.,Department of Biomedical Engineering, College of Health Science, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, Republic of Korea
| | - Ji-Young Hwang
- Department of Biomedical Engineering, College of Health Science, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, Republic of Korea.
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyunggi-do, Republic of Korea.
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Teofili L, Silini AR, Bianchi M, Valentini CG, Parolini O. Incorporating placental tissue in cord blood banking for stem cell transplantation. Expert Rev Hematol 2018; 11:649-661. [PMID: 29856650 DOI: 10.1080/17474086.2018.1483717] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Human term placenta is comprised of various tissues from which different cells can be obtained, including hematopoietic stem cells and mesenchymal stem/stromal cells (MSCs). Areas covered: This review will discuss the possibility to incorporate placental tissue cells in cord blood banking. It will discuss general features of human placenta, with a brief review of the immune cells at the fetal-maternal interface and the different cell populations isolated from placenta, with a particular focus on MSCs. It will address the question as to why placenta-derived MSCs should be banked with their hematopoietic counterparts. It will discuss clinical trials which are studying safety and efficacy of placenta tissue-derived MSCs in selected diseases, and preclinical studies which have proven their therapeutic properties in other diseases. It will discuss banking of umbilical cord blood and raise several issues for improvement, and the applications of cord blood cells in non-malignant disorders. Expert commentary: Umbilical cord blood banking saves lives worldwide. The concomitant banking of non-hematopoietic cells from placenta, which could be applied therapeutically in the future, alone or in combination to their hematopoietic counterparts, could exploit current banking processes while laying the foundation for clinical trials exploring placenta-derived cell therapies in regenerative medicine.
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Affiliation(s)
- Luciana Teofili
- a Policlinico Universitario A. Gemelli IRCCS , Banca del Sangue di Cordone Ombelicale UNICATT, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Antonietta R Silini
- b Centro di Ricerca "E. Menni" Fondazione Poliambulanza - Istituto Ospedaliero , Brescia , Italy
| | - Maria Bianchi
- c Policlinico Universitario A. Gemelli IRCCS, Banca del Sangue di Cordone Ombelicale UNICATT , Rome , Italy
| | | | - Ornella Parolini
- b Centro di Ricerca "E. Menni" Fondazione Poliambulanza - Istituto Ospedaliero , Brescia , Italy.,d Istituto di Anatomia Umana e Biologia Cellulare Facoltà di Medicina e chirurgia "A. Gemelli" , Università Cattolica del Sacro Cuore , Rome , Italy
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