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Sasaki Y, Ohnishi S, Takahashi H, Ishikawa K, Miura T, Funayama E, Okubo N, Yamamoto Y, Maeda T. Extracellular matrix modulating effects of amnion-derived mesenchymal stem cells on aging skin wounds in α-Klotho knockout mice. Geriatr Gerontol Int 2025; 25:701-708. [PMID: 40229127 DOI: 10.1111/ggi.70043] [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: 02/16/2025] [Revised: 03/11/2025] [Accepted: 03/25/2025] [Indexed: 04/16/2025]
Abstract
AIM Wounds in the elderly are frequently recalcitrant and chronic as a result of the effects of skin aging and associated complications. The objective of this study is to utilize an α-Klotho knockout (KO) mice wound model to assess the capacity of amnion-derived mesenchymal stem cells (AMSCs) to facilitate wound healing in aging skin. METHODS AMSCs were applied topically to the wound after extraction and gelatinization of the conditioned medium (CM). Animal experiments were performed with two distinct mouse strains: α-Klotho KO mice and wild-type mice. Full-thickness skin defect models with a diameter of 8 mm were created by incising the skin on the left and right sides of the dorsum. On day 8 after wound creation, the mice were sacrificed, and wound tissue was collected for analysis through histological and immunohistochemical evaluations, as well as through quantitative polymerase chain reaction. RESULTS The topical application of CM gel to wounds of α-Klotho KO mice demonstrated that wound healing was significantly higher than that observed in control, reaching the wound closure rate of wild-type mice on day 8. Additionally, gene expression analysis of wound tissue indicated that AMSC-CM may regulate extracellular matrix formation and fibrosis. Moreover, histological analysis indicated that AMSC-CM may facilitate wound contraction of aging skin wounds of α-Klotho KO mice by inducing myofibroblast differentiation and promoting granulation and collagen formation, which are the primary components of the extracellular matrix. CONCLUSIONS AMSC-CM may facilitate wound healing in aging skin of α-Klotho KO mice by regulating the extracellular matrix. Geriatr Gerontol Int 2025; 25: 701-708.
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Affiliation(s)
- Yuki Sasaki
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan
| | - Hiroko Takahashi
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Kosuke Ishikawa
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Takahiro Miura
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Emi Funayama
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Naoto Okubo
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan
| | - Yuhei Yamamoto
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Taku Maeda
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
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van Rhijn-Brouwer FCCC, Wever KE, Kiffen R, van Rhijn JR, Gremmels H, Fledderus JO, Vernooij RWM, Verhaar MC. Systematic review and meta-analysis of the effect of bone marrow-derived cell therapies on hind limb perfusion. Dis Model Mech 2024; 17:dmm050632. [PMID: 38616715 PMCID: PMC11139036 DOI: 10.1242/dmm.050632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/03/2024] [Indexed: 04/16/2024] Open
Abstract
Preclinical and clinical studies on the administration of bone marrow-derived cells to restore perfusion show conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of bone marrow-derived cells in the hind limb ischemia model and identify possible determinants of therapeutic efficacy. In vivo animal studies were identified using a systematic search in PubMed and EMBASE on 10 January 2022. 85 studies were included for systematic review and meta-analysis. Study characteristics and outcome data on relative perfusion were extracted. The pooled mean difference was estimated using a random effects model. Risk of bias was assessed for all included studies. We found a significant increase in perfusion in the affected limb after administration of bone marrow-derived cells compared to that in the control groups. However, there was a high heterogeneity between studies, which could not be explained. There was a high degree of incomplete reporting across studies. We therefore conclude that the current quality of preclinical research is insufficient (low certainty level as per GRADE assessment) to identify specific factors that might improve human clinical trials.
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Affiliation(s)
| | - Kimberley Elaine Wever
- Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Romy Kiffen
- Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jon-Ruben van Rhijn
- Institute of Life Sciences and Chemistry, HU University of Applied Sciences Utrecht, 3584 CS Utrecht, The Netherlands
| | - Hendrik Gremmels
- Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Joost Ougust Fledderus
- Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Robin Wilhelmus Maria Vernooij
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Marianne Christina Verhaar
- Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
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Master YL, Wei-Meng Tian B, Xing-Fang Jin M, Zong-Liu Hou P, Jing-Ping-Wang B, Yun-Shan Zhang B, Feng-Yun Luo B, Jian-Pei Su M, Jun Wang B, Ming-Hui Meng P, Yan He P. A clinical research of 11cases of human umbilical cord mesenchymal stem cells for curing senile vascular dementia. Transpl Immunol 2022; 74:101669. [PMID: 35835295 DOI: 10.1016/j.trim.2022.101669] [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: 03/10/2022] [Revised: 07/08/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Patients affected by senile vascular dementia (VaD) suffer from a gradual deterioration in their cognitive expressions as well as the ability of taking care for themselves. This study aimed to investigate the clinical efficacy and safety of improving cognitive function and daily life activities of patients with VaD by transplanting human umbilical cord mesenchymal stem cells (HUCMSCs). METHODS A total number of 11 patients with senile VaD, who were admitted through outpatient treatment and hospitalized between February 2013 and February 2016, were selected. The diagnosis was based on CT and MRI examinations. The cultivated HUCMSCs (106 /kg) were injected by intravenous (i.v.) infusion on three occasions. Patients were evaluated for the Mini-Mental State Examination (MMSE) with 25-30 as normal, 21-24 as mild dementia, 10-20 as moderate dementia, and 0-9 as severe dementia. In addition, the Barthel index (BI) was used for a standardized activities of daily living (ADLs) with 0-20 as total dependence, 21-60 as severe dependence, 61-90 as moderate dependence, and 91-95 slight dependence. The t-test was performed to compare statistical significance. RESULTS The study included 11 subjects, one of whom fell out due to an event unrelated to the study. The results show descriptive statistics at different time points. No matter MMSE score or Barthel index, the difference between before treatment and after treatment or follow-up was statistically significant (P < 0.001).Result interpretation: this intervention method has a significant therapeutic effect, and in the 3-month follow-up period, the intervention effect is still significant compared with that before treatment. CONCLUSIONS Our preliminary clinical observations suggest that the i.v. infusion of HUCMSCs significantly improved the cognitive function (MMSE) and daily life activities (BI) of patients with senile VaD. This approach may prove to be safe and relatively simple method to be applied for the treatment of senile VaD.
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Affiliation(s)
- You Li Master
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Wei-Meng Tian
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China.
| | - Master Xing-Fang Jin
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
| | | | - Bachelor Jing-Ping-Wang
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Yun-Shan Zhang
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Feng-Yun Luo
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Master Jian-Pei Su
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Jun Wang
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
| | | | - Postgraduates Yan He
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
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4
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Akita N, Narita Y, Yamawaki-Ogata A, Usui A, Komori K. Therapeutic effect of allogeneic bone marrow-derived mesenchymal stromal cells on aortic aneurysms. Cell Tissue Res 2021; 383:781-793. [PMID: 33146827 DOI: 10.1007/s00441-020-03295-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 09/14/2020] [Indexed: 01/14/2023]
Abstract
We previously reported the effectiveness of autologous mesenchymal stromal cells (MSCs) for the treatment of aortic aneurysm (AA), mediated mainly by these cells' anti-inflammatory properties. In this study, we investigate whether the therapeutic effects of allogeneic MSCs on AA are the same as those of autologous MSCs. To examine the immune response to allogeneic MSCs, C57BL/6 lymphocytes were co-cultured with BALB/c MSCs for 5 days in vitro. Apolipoprotein E-deficient C57BL/6 mice with AA induced by angiotensin II were randomly divided into three groups defined by the following intravenous injections: (i) 0.2 ml of saline (n = 10, group S) as a control, (ii) 1 × 106 autologous MSCs (isolated from C57BL/6, n = 10, group Au) and (iii) 1 × 106 allogeneic MSCs (isolated from BALB/c, n = 10, group Al). Two weeks after injection, aortic diameters were measured, along with enzymatic activities of MMP-2 and MMP-9 and cytokine concentrations in AAs. Neither allogenic (BALB/c) MSCs nor autologous (C57BL/6) MSCs accelerated the proliferation of lymphocytes obtained from C57BL/6. Compared with group S, groups Au and Al had significantly shorter aortic diameters (group S vs Au vs Al; 2.29 vs 1.40 vs 1.36 mm, respectively, p < 0.01), reduced MMP-2 and MMP-9 activities, downregulated IL-6 and MCP-1 and upregulated expression of IGF-1 and TIMP-2. There were no differences in these results between groups Au and Al. Thus, our study suggests that treatment with allogeneic MSCs improves chronic inflammation and reduced aortic dilatation. These effects were equivalent to those of autologous MSCs in established mouse models of AA.
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Affiliation(s)
- Naohiro Akita
- Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuji Narita
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Aika Yamawaki-Ogata
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Akihiko Usui
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Kimihiro Komori
- Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Ishikane S, Ikushima E, Igawa K, Tomooka K, Takahashi-Yanaga F. Differentiation-inducing factor-1 potentiates adipogenic differentiation and attenuates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118909. [PMID: 33189784 DOI: 10.1016/j.bbamcr.2020.118909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/12/2020] [Accepted: 11/10/2020] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem cells (MSCs) are an attractive cell source for tissue regeneration and repair. However, their low differentiation efficacy currently impedes the development of MSC therapy. Therefore, in this study, we investigated the effects of differentiation-inducing factor-1 (DIF-1) on the differentiation efficacy of bone marrow-derived MSCs (BM-MSCs) into adipogenic or osteogenic lineages. BM-MSCs, which were obtained from Sprague-Dawley rats, were positive for the MSC markers (CD29, CD73, and CD90). DIF-1 alone neither affected cell surface antigen expression nor induced adipogenic or osteogenic differentiation. However, DIF-1 significantly enhanced the effects of adipogenic differentiation stimuli, which were evaluated as the number of oil red-O positive cells and the expression of adipocyte differentiation markers (peroxisome proliferator-activated receptor gamma, adipocyte fatty acid-binding protein, and adiponectin). In contrast, DIF-1 significantly attenuated the effects of osteogenic differentiation stimuli, which were evaluated as alizarin red-S positive calcium deposition, and the expression of osteoblast differentiation markers alkaline phosphatase, runt-related transcription factor 2, and osteopontin. We further investigated the mechanism by which DIF-1 affects MSC differentiation efficacy and found that glycogen synthase kinase-3 was the main factor mediating the action of DIF-1 on the adipogenic differentiation of BM-MSCs, whereas it was only partially involved in osteogenic differentiation. These results suggest that DIF-1 supports MSC differentiation toward the desired cell fate by enhancing the differentiation efficacy.
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Affiliation(s)
- Shin Ishikane
- Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, Fukuoka 807-8555, Japan.
| | - Eigo Ikushima
- Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, Fukuoka 807-8555, Japan
| | - Kazunobu Igawa
- Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Chikushi Campus 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
| | - Katsuhiko Tomooka
- Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Chikushi Campus 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
| | - Fumi Takahashi-Yanaga
- Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, Fukuoka 807-8555, Japan
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6
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Okamoto R, Shimizu H, Suzuki K, Kawamoto A, Takahashi J, Kawai M, Nagata S, Hiraguri Y, Takeoka S, Sugihara HY, Yui S, Watanabe M. Organoid-based regenerative medicine for inflammatory bowel disease. Regen Ther 2020; 13:1-6. [PMID: 31970266 PMCID: PMC6961757 DOI: 10.1016/j.reth.2019.11.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/08/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) consists of two major idiopathic gastrointestinal diseases: ulcerative colitis and Crohn's disease. Although a significant advance has been achieved in the treatment of IBD, there remains a particular population of patients that are refractory to the conventional treatments, including the biologic agents. Studies have revealed the importance of "mucosal healing" in improving the prognosis of those difficult-to-treat patients, which indicates the proper and complete regeneration of the damaged intestinal tissue. In this regard, organoid-based regenerative medicine may have the potential to dramatically promote the achievement of mucosal healing in refractory IBD patients, and thereby improve their long-term prognosis as well. So far, studies have shown that hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) may have some beneficial effect on IBD patients through their transplantation or transfusion. Recent advance in stem cell biology has added intestinal stem cells (ISCs) as a new player in this field. It has been shown that ISCs can be grown in vitro as organoids and that those ex-vivo cultured organoids can be employed as donor cells for transplantation studies. Further studies using mice colitis models have shown that ex-vivo cultured organoids can engraft onto the colitic ulcers and reconstruct the crypt-villus structures. Such transplantation of organoids may not only facilitate the regeneration of the refractory ulcers that may persist in IBD patients but may also reduce the risk of developing colitis-associated cancers. Endoscopy-assisted transplantation of organoids may, therefore, become one of the alternative therapies for refractory IBD patients.
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Affiliation(s)
- Ryuichi Okamoto
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kohei Suzuki
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Junichi Takahashi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mao Kawai
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sayaka Nagata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yui Hiraguri
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sayaka Takeoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hady Yuki Sugihara
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shiro Yui
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mamoru Watanabe
- Institute of Advanced Study, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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7
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Park HS, Ashour D, Elsharoud A, Chugh RM, Ismail N, El Andaloussi A, Al-Hendy A. Towards Cell free Therapy of Premature Ovarian Insufficiency: Human Bone Marrow Mesenchymal Stem Cells Secretome Enhances Angiogenesis in Human Ovarian Microvascular Endothelial Cells. ACTA ACUST UNITED AC 2019; 5. [PMID: 32494757 PMCID: PMC7269190 DOI: 10.24966/srdt-2060/100019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Primary Ovarian Insufficiency (POI) refers to an ovarian loss of function in women under the age of 40. Unfortunately, currently, there is no effective treatment available for POI-related infertility. Alternatives such as the use of egg donations are culturally and ethically unacceptable to many couples. Human Bone marrow-derived Mesenchymal Stem Cells (MSCs) are known for their ability to differentiate into other cell types, once primed by the organ microenvironment. Importantly MSCs produce a vast array of bioactive factors many of them have been shown to enhance neovascularization in various tissues. Recently, preliminary data from our ongoing clinical trial revealed encouraging preliminary data after autologous MSC engraftment into the ovaries of 2 POI patients with durable elevation in serum estrogen levels and increase in size of treated ovaries sustained up to one-year post cell therapy. In this study, we investigated the action of the mechanisms of MSCs treatment on a POI ovary. We designed an in vitro study using MSC secretome and Human Ovarian Endothelial Cells (HOVECs) to understand the molecular mechanisms by which MSC mediates their angiogenic properties and regenerative effects. Human primary HOVECs were treatment with MSC secretome and examined by FACS for the expression of angiogenesis markers such as Endoglin, Tie-2, and VEGF. The formation of vessels was evaluated by using a 3D Matrigel tubulogenesis assay. We observed that the expression of proliferation marker Ki67 was significantly increased under treatment with MSC secretome in HOVEC cells (P4). MSCs secretome treatment also induced significantly higher expression of several angiogenic markers such as VEGFR2, Tie2/Tek, VE-Cadherin, Endoglin, and VEGF compared to matched control (P4). Furthermore, MSC secretome significantly increased the number of branching points in tubulogenesis assay (P4). Our study suggests that MSC secretome likely contains bioactive factors that can enhance ovarian angiogenesis. Further characterization of these factors can lead to novel therapeutic options for women with premature ovarian insufficiency and other related causes of female infertility.
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Affiliation(s)
- Hang-Soo Park
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Dalia Ashour
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA.,Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Amro Elsharoud
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Rishi Man Chugh
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Nahed Ismail
- Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | | | - Ayman Al-Hendy
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
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Wang Y, Tian M, Wang F, Heng BC, Zhou J, Cai Z, Liu H. Understanding the Immunological Mechanisms of Mesenchymal Stem Cells in Allogeneic Transplantation: From the Aspect of Major Histocompatibility Complex Class I. Stem Cells Dev 2019; 28:1141-1150. [PMID: 31215341 DOI: 10.1089/scd.2018.0256] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) transplantation therapy appears to be an ideal strategy for repairing structural defects and restoring the functions of diseased tissues and organs. Additionally, MSCs are also used as immunosuppressants in allogeneic organ transplantation. However, owing to their inherent immunogenicity, MSC transplantation can induce the activation of an immune response, which can lead to the death and clearance of the transplanted MSCs. Major histocompatibility complex (MHC) molecules are responsible for antigen presentation, help T lymphocytes to recognize endogenous/extrinsic antigens, and trigger immune activation. Many studies have shown that MHC molecules (particularly class I) play key roles in the immunogenicity of MSCs. This review, therefore, focuses on the relationship between MHC-I surface expression on MSCs and its immunogenicity, as well as potential strategies to overcome the hurdle of MHC incompatibility.
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Affiliation(s)
- Yafei Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Mengya Tian
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Fei Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Boon Chin Heng
- School of Stomatology, Peking University, Beijing, China
| | - Jing Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Zhijian Cai
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hua Liu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China
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9
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Kobayashi K, Ichihara Y, Sato N, Umeda N, Fields L, Fukumitsu M, Tago Y, Ito T, Kainuma S, Podaru M, Lewis-McDougall F, Yamahara K, Uppal R, Suzuki K. On-site fabrication of Bi-layered adhesive mesenchymal stromal cell-dressings for the treatment of heart failure. Biomaterials 2019; 209:41-53. [PMID: 31026610 PMCID: PMC6527869 DOI: 10.1016/j.biomaterials.2019.04.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal/stem cell (MSC)-based therapy is a promising approach for the treatment of heart failure. However, current MSC-delivery methods result in poor donor cell engraftment, limiting the therapeutic efficacy. To address this issue, we introduce here a novel technique, epicardial placement of bi-layered, adhesive dressings incorporating MSCs (MSC-dressing), which can be easily fabricated from a fibrin sealant film and MSC suspension at the site of treatment. The inner layer of the MSC dressing, an MSC-fibrin complex, promptly and firmly adheres to the heart surface without sutures or extra glues. We revealed that fibrin improves the potential of integrated MSCs through amplifying their tissue-repair abilities and activating the Akt/PI3K self-protection pathway. Outer collagen-sheets protect the MSC-fibrin complex from abrasion by surrounding tissues and also facilitates easy handling. As such, the MSC-dressing technique not only improves initial retention and subsequent maintenance of donor MSCs but also augment MSC's reparative functions. As a result, this technique results in enhanced cardiac function recovery with improved myocardial tissue repair in a rat ischemic cardiomyopathy model, compared to the current method. Dose-dependent therapeutic effects by this therapy is also exhibited. This user-friendly, highly-effective bioengineering technique will contribute to future success of MSC-based therapy.
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Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Yuki Ichihara
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Nobuhiko Sato
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom; Kaneka Corporation, Osaka, Japan
| | | | - Laura Fields
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Masafumi Fukumitsu
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | | | - Tomoya Ito
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Satoshi Kainuma
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Mihai Podaru
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Fiona Lewis-McDougall
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Kenichi Yamahara
- Transfusion Medicine and Cellular Therapy, Hyogo College of Medicine, Japan
| | - Rakesh Uppal
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Ken Suzuki
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom.
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10
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García-Vázquez MD, Herrero de la Parte B, García-Alonso I, Morales MC. [Analysis of Biological Properties of Human Adult Mesenchymal Stem Cells and Their Effect on Mouse Hind Limb Ischemia]. J Vasc Res 2019; 56:77-91. [PMID: 31079101 DOI: 10.1159/000498919] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 02/13/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Due to their self-renewal, proliferation, differentiation, and angiogenesis-inducing capacity, human adipose mesenchymal stem cells (AMSC) have potential clinical applications in the treatment of limb ischemia. AMSC from healthy donors have been shown to induce neovascularization in animal models. However, when cells were obtained from donors suffering from any pathology, their autologous application showed limited effectiveness. We studied whether liposuction niche and obesity could determine the regenerative properties of cells meaning that not all cell batches are suitable for clinical practice. METHODS AMSC obtained from 10 donors, obese and healthy, were expanded in vitro following a good manufacturing practice-like production protocol. Cell viability, proliferation kinetics, morphological analysis, phenotype characterization, and stemness potency were assessed over the course of the expansion process. AMSC selected for having the most suitable biological properties were used as an experimental treatment in a preclinical mouse model of hind limb ischemia. RESULT All cell batches were positively characterized as mesenchymal stem cells, but not all of them showed the same properties or were successfully expanded in vitro, depending on the characteristics of the donor and the extraction area. Notably, AMSC from the abdomen of obese donors showed undesirable biological properties. AMSC with low duplication times and multilineage differentiation potential and forming large densely packed colonies, were able, following expansion in vitro, to increase neovascularization and repair when implanted in the ischemic tissue of mice. CONCLUSION An extensive AMSC biological properties study could be useful to predict the potential clinical efficacy of cells before in vivo transplantation. Thus, peripheral ischemia and possibly other pathologies could benefit from stem cell treatments as shown in our preclinical model in terms of tissue damage repair and regeneration after ischemic injury.
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Affiliation(s)
| | - Borja Herrero de la Parte
- Department of Surgery and Radiology and Physical Medicine, University of the Basque Country, Leioa, Spain
| | - Ignacio García-Alonso
- Department of Surgery and Radiology and Physical Medicine, University of the Basque Country, Leioa, Spain
| | - María-Celia Morales
- Department of Cell Biology and Histology, University of the Basque Country, Leioa, Spain,
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11
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Hamidian Jahromi S, Davies JE. Concise Review: Skeletal Muscle as a Delivery Route for Mesenchymal Stromal Cells. Stem Cells Transl Med 2019; 8:456-465. [PMID: 30720934 PMCID: PMC6477141 DOI: 10.1002/sctm.18-0208] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have demonstrated extensive capacity to modulate a catabolic microenvironment toward tissue repair. The fate, biodistribution, and dwell time of the in vivo delivered MSCs largely depend on the choice of the cell delivery route. Intramuscular (IM) delivery of MSCs is clinically safe and has been used for the effective treatment of local pathologies. Recent findings have shown that the secretome of the IM‐delivered MSCs enters the circulation and provides systemic effects on distant organs. In addition, muscle tissue provides a safe residence for the delivered MSCs and an extended secretorily active dwell time compared with other delivery routes. There are, however, controversies concerning the fate of MSCs post IM‐delivery and, specifically, into an injured site with proinflammatory cues. This review seeks to provide a brief overview of the fate and efficacy of IM‐delivered MSCs and to identify the gaps that require further assessment for adoption of this promising route in the treatment of systemic disease. stem cells translational medicine2019;8:456–465
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Affiliation(s)
- Shiva Hamidian Jahromi
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - John E Davies
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Canada
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12
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Yang Z, He LJ, Sun SR. Role of Endothelial Cells in Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:145-163. [PMID: 31399965 DOI: 10.1007/978-981-13-8871-2_8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Renal fibrosis has been regarded as the common pathway of end-stage renal failure. Understanding the fundamental mechanism that leads to renal fibrosis is essential for developing better therapeutic options for chronic kidney diseases. So far, the main abstractions are on the injury of tubular epithelial cells, activation of interstitial cells, expression of chemotactic factor and adhesion molecule, infiltration of inflammatory cells and homeostasis of ECM. However, emerging studies revealed that endothelial cells (ECs) might happen to endothelial-to-mesenchymal transition (EndMT) dependent and/or independent endothelial dysfunction, which were supposed to accelerate renal fibrosis and are identified as new mechanisms for the proliferation of myofibroblasts as well. In this chapter, we are about to interpret the role of ECs in renal fibrosis and analyze the related molecules and pathways of both EndMT and EndMT independent endothelial dysfunction.
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Affiliation(s)
- Zhen Yang
- Department of Nephrology, The First Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi, China
| | - Li-Jie He
- Department of Nephrology, The First Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi, China
| | - Shi-Ren Sun
- Department of Nephrology, The First Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi, China.
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13
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Enhancement of the efficacy of mesenchymal stem cells in the treatment of ischemic diseases. Biomed Pharmacother 2018; 109:2022-2034. [PMID: 30551458 DOI: 10.1016/j.biopha.2018.11.068] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 02/05/2023] Open
Abstract
Ischemic diseases refer to a wide range of diseases caused by reduced blood flow and a subsequently deficient oxygen and nutrient supply. The pathogenesis of ischemia is multifaceted and primarily involves inflammation, oxidative stress and an apoptotic response. Over the last decade, mesenchymal stem cells (MSCs) have been widely studied as potential cell therapy agents for ischemic diseases due to their multiple favourable functions. However, the low homing and survival rates of transplanted cells have been concerns limiting for their clinical application. Recently, increasing studies have attempted to enhance the efficacy of MSCs by various strategies including genetic modification, pretreatment, combined application and biomaterial application. The purpose of this review is to summarize these creative strategies and the progress in basic and preclinical studies.
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14
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Murata Y, Jo JI, Tabata Y. Preparation of cationized gelatin nanospheres incorporating molecular beacon to visualize cell apoptosis. Sci Rep 2018; 8:14839. [PMID: 30287861 PMCID: PMC6172245 DOI: 10.1038/s41598-018-33231-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 09/17/2018] [Indexed: 12/16/2022] Open
Abstract
The objective of this study is to prepare cationized gelatin nanospheres (cGNS) incorporating a molecular beacon (MB), and visualize cellular apoptosis. Two types of MB to detect the messenger RNA (mRNA) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (GAP MB), and caspase-3 (casp3 MB) were incorporated in cGNS, respectively. MB incorporated in cGNS showed the DNA sequence specificity in hybridization. The cGNS incorporation enabled MB to enhance the stability against nuclease to a significantly great extent compared with free MB. The cGNS incorporating GAP MB were internalized into the KUM6 of a mouse bone marrow-derived stem cell by an endocytotic pathway. The cGNS were not distributed at the lysosomes. After the incubation with cGNS, the cell apoptosis was induced at different concentrations of camptothecin. No change in the intracellular fluorescence was observed for cGNSGAPMB. On the other hand, for the cGNScasp3MB, the fluorescent intensity significantly enhanced by the apoptosis induction of cells. It is concluded that cGNS incorporating MB is a promising system for the visualization of cellular apoptosis.
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Affiliation(s)
- Yuki Murata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Jun-Ichiro Jo
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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15
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Hamzei Taj S, Le Blon D, Hoornaert C, Daans J, Quarta A, Praet J, Van der Linden A, Ponsaerts P, Hoehn M. Targeted intracerebral delivery of the anti-inflammatory cytokine IL13 promotes alternative activation of both microglia and macrophages after stroke. J Neuroinflammation 2018; 15:174. [PMID: 29866203 PMCID: PMC5987479 DOI: 10.1186/s12974-018-1212-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 05/21/2018] [Indexed: 12/27/2022] Open
Abstract
Background Subtle adjustment of the activation status of CNS resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards curing neurodegenerative disorders. In the present study, we investigated whether targeted intracerebral delivery of the anti-inflammatory cytokine interleukin (IL)13, by means of transplanting IL13-expressing mesenchymal stem cells (IL13-MSCs), can promote a phenotypic switch in both microglia and macrophages during the pro-inflammatory phase in a mouse model of ischemic stroke. Methods We used the CX3CR1eGFP/+ CCR2RFP/+ transgenic mouse model to separately recognize brain-resident microglia from infiltrated macrophages. Quantitative immunohistochemical analyses were applied to characterize polarization phenotypes of both cell types. Results Distinct behaviors of both cell populations were noted dependent on the anatomical site of the lesion. Immunohistochemistry revealed that mice grafted with IL13-MSCs, in contrast to non-grafted and MSC-grafted control mice, were able to drive recruited microglia and macrophages into an alternative activation state, as visualized by a significant increase of Arg-1 and a noticeable decrease of MHC-II expression at day 14 after ischemic stroke. Interestingly, both Arg-1 and MHC-II were expressed more abundantly in macrophages than in microglia, further confirming the distinct behavior of both cell populations. Conclusions The current data highlight the importance of controlled and localized delivery of the anti-inflammatory cytokine IL13 for modulation of both microglia and macrophage responses after ischemic stroke, thereby providing pre-clinical rationale for the application of L13-MSCs in future investigations of neurodegenerative disorders. Electronic supplementary material The online version of this article (10.1186/s12974-018-1212-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Somayyeh Hamzei Taj
- In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, D-50931, Köln, Germany
| | - Debbie Le Blon
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Chloé Hoornaert
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Jasmijn Daans
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Alessandra Quarta
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Jelle Praet
- Bio-Imaging Laboratory, University of Antwerp, Antwerp, Belgium
| | | | - Peter Ponsaerts
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Mathias Hoehn
- In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, D-50931, Köln, Germany. .,Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
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16
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Lee SG, Joe YA. Autophagy mediates enhancement of proangiogenic activity by hypoxia in mesenchymal stromal/stem cells. Biochem Biophys Res Commun 2018; 501:941-947. [PMID: 29772235 DOI: 10.1016/j.bbrc.2018.05.086] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 05/14/2018] [Indexed: 01/07/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) have been promising source for regenerative cell therapy in ischemic diseases. To improve efficacy of MSC therapy, various priming methods have been developed, and hypoxic priming has been reported to enhance therapeutic efficacy of MSCs by increasing secretion level of growth factors and cytokines. Recently, it has been reported that bone marrow MSCs primed with hypoxic condition show an increase of autophagy. Here, we addressed whether proangiogenic activity increased by hypoxic condition is associated with autophagy. Wharton's jelly derived MSCs primed with hypoxia showed increase of autophagy with increased hypoxia inducible factor-1α level, and conditioned medium (CM) derived from these cells showed increased levels of migration and tube formation of human umbilical vein endothelial cells (HUVECs) compared to non-primed MSCs-derived CM. Pretreatment with autophagy inhibitor 3-methyladenine or chloroquine prior to exposure of hypoxia resulted in reduction of migration and tube formation of HUVECs. CM obtained under hypoxic condition from MSCs in which autophagy activity was inhibited by ATG5 and ATG7 siRNA treatment also showed decrease of migration and tube formation of HUVECs. Accordingly, secretion levels of angiogenin and VEGF that were markedly increased upon hypoxia exposure was decreased by ATG5/7 knockdown. Therefore, it may be suggested that autophagy plays an important role in hypoxia-driven enhancement of paracrine effect of MSCs.
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Affiliation(s)
- Seul-Gi Lee
- Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Young Ae Joe
- Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
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17
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Orekhov PY, Konoplyannikov MA, Baklaushev VP, Kalsin VAA, Averyanov AV, Konopliannikov AG, Habazov RI, Troitskiy AV. Bone marrow stem cells for the critical limb ischemia treatment: biological aspects and clinical application. GENES & CELLS 2018; 13:20-34. [DOI: 10.23868/201805002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2025]
Abstract
Cell therapy is one of the most promising directions in the treatment of critical limb ischemia (CLI). In spite of certain advances achieved in this field in the last decades, which are related to application of bone marrow stem cells (BMSC), a large number of problems still remain unsolved. In this review, we discuss the BMSC biology, mechanisms of their therapeutic effect in the CLI treatment and results of the most notable BMSC-based clinical studies in detail.
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18
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Arutyunyan IV, Fatkhudinov TK, Elchaninov AV, Makarov AV, Vasyukova OA, Usman NY, Marey MV, Volodina MA, Kananykhina EY, Lokhonina AV, Bolshakova GB, Goldshtein DV, Sukhikh GT. Understanding mechanisms of the umbilical cord-derived multipotent mesenchymal stromal cell-mediated recovery enhancement in rat model of limb ischemia. GENES & CELLS 2018; 13:82-89. [DOI: 10.23868/201805010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Umbilical cord-derived multipotent mesenchymal stromal cells (UC-MMSCs) are considered as a strong candidate for cell therapy of lower limb ischemia. Sustained calf muscle ischemia with aseptic inflammatory response was induced in Sprague-Dawley rats by excision of femoral and popliteal arteries. uC-MSCs were injected into the calf muscle on day 7 after surgery. The animals were sacrificed on days 3, 10, and 30 after transplantation. Animals responded to the transplantation by temporary improvement in their locomotor function as assessed by the rota-rod performance test. Measured size of the lesions was significantly smaller in the experimental group than in the control group at all time points throughout the observation. The transplantation stimulated angiogenic processes on day 10 after transplantation. Living transplanted cells were traced for up to 30 days after transplantation, during which time they migrated to the damaged area to be partially eliminated by host macrophages; none of them differentiated into endothelial or smooth muscle cells of blood vessels. Additionally, the transplantation led to the predominance of activated pro-angiogenic and anti-inflammatory M2 macrophages by inhibiting the CD68+ macrophage infiltration and stimulating the CD206+ macrophage activation at the site of injury. A single intramuscular injection of allogeneic umbilical cord-derived mesenchymal stromal cells reproducibly facilitated recovery of structural and functional properties of surgically ischemized calf muscles in a rat. No differentiation of the transplanted cells in vivo was observed. The transplantation negatively regulated inflammation and enhanced tissue repair chiefly by modulating local patterns of macrophage activation.
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19
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Ichihara Y, Kaneko M, Yamahara K, Koulouroudias M, Sato N, Uppal R, Yamazaki K, Saito S, Suzuki K. Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure. Biomaterials 2018; 154:12-23. [PMID: 29117575 PMCID: PMC5768325 DOI: 10.1016/j.biomaterials.2017.10.050] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 09/19/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022]
Abstract
Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix® (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly-produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce "instant" 2PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM-MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart.
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Affiliation(s)
- Yuki Ichihara
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Masahiro Kaneko
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Kenichi Yamahara
- Transfusion Medicine and Cellular Therapy, Hyogo College of Medicine, Japan
| | - Marinos Koulouroudias
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Nobuhiko Sato
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; Kaneka Corporation, Osaka, Japan
| | - Rakesh Uppal
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Kenji Yamazaki
- Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Satoshi Saito
- Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Ken Suzuki
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
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20
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A Molecular and Clinical Review of Stem Cell Therapy in Critical Limb Ischemia. Stem Cells Int 2017; 2017:3750829. [PMID: 29358955 PMCID: PMC5735649 DOI: 10.1155/2017/3750829] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/05/2017] [Indexed: 12/20/2022] Open
Abstract
Peripheral artery disease (PAD) is one of the major vascular complications in individuals suffering from diabetes and in the elderly that can progress to critical limb ischemia (CLI), portending significant burden in terms of patient morbidity and mortality. Over the last two decades, stem cell therapy (SCT) has risen as an attractive alternative to traditional surgical and/or endovascular revascularization to treat this disorder. The primary benefit of SCT is to induce therapeutic neovascularization and promote collateral vessel formation to increase blood flow in the ischemic limb and soft tissue. Existing evidence provides a solid rationale for ongoing in-depth studies aimed at advancing current SCT that may change the way PAD/CLI patients are treated.
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21
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Zhang Y, Zhang H, Ding L, Zhang H, Zhang P, Jiang H, Tan B, Deng Z. MRI reveals slow clearance of dead cell transplants in mouse forelimb muscles. Mol Med Rep 2017; 16:4068-4074. [PMID: 28765924 PMCID: PMC5646989 DOI: 10.3892/mmr.2017.7100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 07/07/2017] [Indexed: 12/23/2022] Open
Abstract
A small molecule tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd‑DOTA)4‑TPP agent is used to label human mesenchymal stem cells (hMSCs) via electroporation (EP). The present study assessed the cytotoxicity of cell labeling, in addition to its effect on cell differentiation potential. There were no significant adverse effects on cell viability or differentiation induced by either EP or cellular uptake of (Gd‑DOTA)4‑TPP. Labeled live and dead hMSCs were transplanted into mouse forelimb muscles. T2‑weighted magnetic resonance imaging (MRI) was used to track the in vivo fate of the cell transplants. The labeling and imaging strategy allowed long term tracking of the cell transplants and unambiguous distinguishing of the cell transplants from their surrounding tissues. Cell migration was observed for live hMSCs injected into subcutaneous tissues, however not for either live or dead hMSCS injected into limb muscles. A slow clearance process occurred of the dead cell transplants in the limb muscular tissue. The MRI results therefore reveal that the fate and physiological activities of cell transplants depend on the nature of their host tissue.
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Affiliation(s)
- Yanhui Zhang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Hongyan Zhang
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
- Institute of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, P.R. China
| | - Lijun Ding
- Center for Reproductive Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Hailu Zhang
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Pengli Zhang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Haizhen Jiang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
| | - Bo Tan
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Zongwu Deng
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
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22
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Mooney R, Abdul Majid A, Batalla J, Annala AJ, Aboody KS. Cell-mediated enzyme prodrug cancer therapies. Adv Drug Deliv Rev 2017; 118:35-51. [PMID: 28916493 DOI: 10.1016/j.addr.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/15/2017] [Accepted: 09/06/2017] [Indexed: 02/08/2023]
Abstract
Cell-directed gene therapy is a promising new frontier for the field of targeted cancer therapies. Here we discuss the current pre-clinical and clinical use of cell-mediated enzyme prodrug therapy (EPT) directed against solid tumors and avenues for further development. We also discuss some of the challenges encountered upon translating these therapies to clinical trials. Upon sufficient development, cell-mediated enzyme prodrug therapy has the potential to maximize the distribution of therapeutic enzymes within the tumor environment, localizing conversion of prodrug to active drug at the tumor sites thereby decreasing off-target toxicities. New combinatorial possibilities are also promising. For example, when combined with viral gene-delivery vehicles, this may result in new hybrid vehicles that attain heretofore unmatched levels of therapeutic gene expression within the tumor.
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23
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Mizushima T, Ohnishi S, Hosono H, Yamahara K, Tsuda M, Shimizu Y, Kato M, Asaka M, Sakamoto N. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointest Endosc 2017; 86:542-552.e1. [PMID: 28153569 DOI: 10.1016/j.gie.2017.01.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 01/16/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD. METHODS We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis. RESULTS Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8. CONCLUSIONS CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.
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Affiliation(s)
- Takeshi Mizushima
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hidetaka Hosono
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Yamahara
- Department of Transfusion Medicine and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Japan
| | - Momoko Tsuda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yuichi Shimizu
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Mototsugu Kato
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Masahiro Asaka
- Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Álvarez García J, García Gómez-Heras S, Riera del Moral L, Largo C, García-Olmo D, García-Arranz M. The effects of allogenic stem cells in a murine model of hind limb diabetic ischemic tissue. PeerJ 2017; 5:e3664. [PMID: 28852591 PMCID: PMC5572534 DOI: 10.7717/peerj.3664] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 07/18/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Diabetes is one of the major risk factors for peripheral arterial disease. In patients in whom surgery cannot be performed, cell therapy may be an alternative treatment. Since time is crucial for these patients, we propose the use of allogenic mesenchymal cells. METHODS We obtained mesenchymal cells derived from the fat tissue of a healthy Sprague-Dawley rat. Previous diabetic induction with streptozotocin in 40 male Sprague-Dawley rats, ligation plus left iliac and femoral artery sections were performed as a previously described model of ischemia. After 10 days of follow-up, macroscopic and histo-pathological analysis was performed to evaluate angiogenic and inflammatory parameters in the repair of the injured limb. All samples were evaluated by the same blind researcher. Statistical analysis was performed using the SPSS v.11.5 program (P < 0.05). RESULTS Seventy percent of the rats treated with streptozotocin met the criteria for diabetes. Macroscopically, cell-treated rats presented better general and lower ischemic clinical status, and histologically, a better trend towards angiogenesis, greater infiltration of type 2 macrophages and a shortening of the inflammatory process. However, only the inflammatory variables were statistically significant. No immunological reaction was observed with the use of allogeneic cells. DISCUSSION The application of allogeneic ASCs in a hind limb ischemic model in diabetic animals shows no rejection reactions and a reduction in inflammatory parameters in favor of better repair of damaged tissue. These results are consistent with other lines of research in allogeneic cell therapy. This approach might be a safe, effective treatment option that makes it feasible to avoid the time involved in the process of isolation, expansion and production of the use of autologous cells.
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Affiliation(s)
| | - Soledad García Gómez-Heras
- Department of Human Hystology, Health Science Faculty, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | | | - Carlota Largo
- Experimental Surgery Department, Hospital Universitario La Paz, Madrid, Spain
| | - Damián García-Olmo
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Surgery, Hospital Universitario Fundación Jimenéz Díaz, Madrid, Spain
| | - Mariano García-Arranz
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
- New Therapies Lab, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
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Adipose-Derived Cell Transplantation in Systemic Sclerosis: State of the Art and Future Perspectives. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2016. [DOI: 10.5301/jsrd.5000222] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Systemic sclerosis (SSc) is one of the most complex connective tissue diseases. Although significant progress in the knowledge of pathogenic mechanisms and timely diagnosis, therapeutic options remain limited. The attempt to find new treatments for SSc has led researchers to investigate the potential of cellular therapies using autologous and allogeneic stem cells. Multipotent mesenchymal stromal cells (MSCs) are considered an attractive candidate for cell-based therapies. MSCs comprise a heterogeneous population of cells with multilineage differentiation potential that are preferentially able to home to the sites of damage, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. MSCs from bone-marrow have been first extensively characterized. Adipose tissue represents an additional abundant and accessible source of stem cells. Compared with BM-MSCs, adipose-derived stromal/stem cells (ASCs) offer several advantages, including ease of isolation, less donor morbidity, relative abundance, and rapidity of expansion. For all these reasons, at present ASCs are one of the most attractive and promising sources of adult stem cells for cell therapy, finding a field of application in the treatment of SSc, too. This review will focus on the current applications and possible future perspectives of adipose tissue-cell therapies in SSc.
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Taki T, Masumoto H, Funamoto M, Minakata K, Yamazaki K, Ikeda T, Sakata R. Fetal mesenchymal stem cells ameliorate acute lung injury in a rat cardiopulmonary bypass model. J Thorac Cardiovasc Surg 2016; 153:726-734. [PMID: 27838010 DOI: 10.1016/j.jtcvs.2016.10.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 09/20/2016] [Accepted: 10/07/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Systemic inflammation after prolonged cardiopulmonary bypass (CPB) can cause serious multiorgan system dysfunction. Mesenchymal stem cells (MSCs) are reported to reduce inflammation and attenuate immune response. We have focused on fetal membrane (FM) as a source to provide a large number of MSCs (FM-MSCs). Allogeneic administration of FM-MSCs has been reported to mitigate autoimmune myocarditis or glomerulonephritis. The aim of this study was to investigate whether allogeneic FM-MSCs attenuate systemic inflammatory responses and lung injury in a rat CPB model. METHODS Male Lewis rats (major histocompatibility complex haplotype: RT-1l) were divided randomly into 3 groups (n = 7 each): cannulation alone (sham group), CPB alone (control group), and CPB + MSC (MSC group). An experimental rat CPB model was established, and CPB was maintained for 30 minutes. In the MSC group, MSCs (1 × 106 cells) derived from the FM of ACI rats with a different major histocompatibility complex haplotype (RT-1a) were administrated intravenously before CPB initiation. RESULTS Serum concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-1β in the MSC group were significantly lower compared with the control group after CPB. Similarly, mRNA expression of proinflammatory cytokines in the lung was lower in the MSC group. Allogeneic administration of FM-MSCs remarkably decreased the lung injury score, protected alveolar structure, inhibited neutrophil infiltration to the lung interstitium, and stimulated cytoprotective cytokine production in the lung. CONCLUSIONS Allogeneic transplantation of FM-MSCs may be a potent strategy to prevent CPB-induced systemic inflammation and acute lung injury by suppressing the expression of inflammatory cytokines and promoting protective factors in the lung.
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Affiliation(s)
- Tomofumi Taki
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hidetoshi Masumoto
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Masaki Funamoto
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Minakata
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuhiro Yamazaki
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tadashi Ikeda
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryuzo Sakata
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Elshaer SL, Lorys RE, El-Remessy AB. Cell Therapy and Critical Limb Ischemia: Evidence and Window of Opportunity in Obesity. ACTA ACUST UNITED AC 2016; 3. [PMID: 28979948 DOI: 10.15226/2374-8354/3/1/00121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Sally L Elshaer
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia 30912, USA
| | - Renee E Lorys
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia 30912, USA
| | - A B El-Remessy
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia 30912, USA
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Non-coding RNA as mediators in microenvironment–breast cancer cell communication. Cancer Lett 2016; 380:289-95. [PMID: 26582656 DOI: 10.1016/j.canlet.2015.11.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/04/2015] [Accepted: 11/06/2015] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment has a critical role in the survival and decision of the cancer cells. These include support by enhanced angiogenesis, and metastasis or adaptation of dormancy. This article discusses methods by which the microenvironment sustains the tumor. This process is important as it will identify avenues of drug targets. Non-coding RNAs (ncRNAs) are evolving as key mediators in the interaction between the cancer cells and the microenvironment. Thus, the question is how to develop methods to effectively block the effects of the ncRNA and/or to introduce them to prevent metastasis, dormancy or to reverse dormancy. We focused on the advantages of using mesenchymal stem cells (MSCs) for RNA delivery. MSCs can be available as "off-the-shelf" cells. Thus far, MSCs are shown to be safe when transplanted across allogeneic barriers. We discussed the various methods by which MSCs can interact with cancer cells to deliver ncRNA or antagomirs. We also include the advances and possible confounds of using these methods. Overall, this review article provides a potential method by which MSCs can be used for effective delivery of nucleic acid to treat cancer.
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Farah Z, Fan H, Liu Z, He JQ. A concise review of common animal models for the study of limb regeneration. Organogenesis 2016; 12:109-118. [PMID: 27391218 DOI: 10.1080/15476278.2016.1205775] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Correct selection of an appropriate animal mode to closely mimic human extremity diseases or to exhibit desirable phenotypes of limb regeneration is the first critical step for all scientists in biomedical and regenerative researches. The commonly-used animals in limb regeneration and repairing studies, such as axolotl, mice, and rats, are discussed in the review and other models including cockroaches, dogs, and horses are also mentioned. The review weighs the general advantages, disadvantages, and precedent uses of each model in the context of limb and peripheral injury and subsequent regeneration. We hope that this review can provide the reader an overview of each model, from which to select one for their specific purpose.
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Affiliation(s)
- Zayd Farah
- a Department of Biomedical Sciences & Pathobiology , Center for Veterinary Regenerative Medicine (CVRM), Virginia-Maryland College of Veterinary Medicine, Virginia Tech , Blacksburg , VA , USA
| | - Huimin Fan
- b Research Institute of Heart Failure , Shanghai East Hospital of Tongji University , Shanghai , China
| | - Zhongmin Liu
- b Research Institute of Heart Failure , Shanghai East Hospital of Tongji University , Shanghai , China
| | - Jia-Qiang He
- a Department of Biomedical Sciences & Pathobiology , Center for Veterinary Regenerative Medicine (CVRM), Virginia-Maryland College of Veterinary Medicine, Virginia Tech , Blacksburg , VA , USA
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30
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Kawakubo K, Ohnishi S, Fujita H, Kuwatani M, Onishi R, Masamune A, Takeda H, Sakamoto N. Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis. Pancreas 2016; 45:707-713. [PMID: 26646279 DOI: 10.1097/mpa.0000000000000541] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine and can be isolated from fetal membranes (FMs), particularly amniotic membranes. We investigated the effect of rat FM-derived MSCs (rFM-MSCs) and human amnion-derived MSCs (hAMSCs) on the inflammatory reaction in vitro and therapeutic effects in rats with acute and chronic pancreatitis. METHODS Effect of rFM-MSCs or hAMSC-conditioned medium was investigated in vitro. Acute pancreatitis was induced by intraductal injection of 4% taurocholate, and rFM-MSCs were transplanted intravenously. Chronic pancreatitis was induced by intravenous injection of 5 mg/kg dibutyltin dichloride, and hAMSCs were transplanted intravenously. RESULTS The inflammatory reaction of macrophages induced by lipopolysaccharide and trypsin was significantly suppressed by rFM-MSC coculture. Pancreatic acinar cell injury induced by cerulein was significantly ameliorated by hAMSC-conditioned medium. Pancreatic stellate cell activation induced by tumor necrosis factor-α was significantly decreased by hAMSC-conditioned medium. Transplantation of rFM-MSCs significantly reduced the histological score and infiltration of CD68-positive macrophages in the rat pancreas. The hAMSC transplantation significantly decreased the expression of MCP-1 and attenuated the downregulation of amylase expression in the pancreas. CONCLUSIONS Transplantation of FM-MSCs and AMSCs suppressed the inflammatory reaction of acute and chronic pancreatitis in rats.
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Affiliation(s)
- Kazumichi Kawakubo
- From the *Department of Gastroenterology and Hepatology, Graduate School of Medicine, †Laboratory of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; and ‡Division of Gastroenterology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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Abstract
INTRODUCTION Advances in immuno-modulatory therapies, including anti-TNF-α therapies, have greatly increased the chance to achieve long-term remission of inflammatory bowel disease (IBD) patients. However, as the importance of mucosal healing has been demonstrated in a number of clinical studies, new cell-based therapies that can regenerate and fully restore the intestinal mucosal functions are currently under development. AREA COVERED In this review, we feature the recent challenges of cell-based therapies that are applied to the treatment of IBD. In particular, we will focus on hematopoietic stem cells (HSC), mesenchymal stem cells (MSCs) and intestinal stem cells (ISCs) as the candidate source for cell-based therapy targeted to treat IBD. The current status, as well as the expected advantages and disadvantages of those transplantations will be summarized and discussed. EXPERT OPINION Transplantation of HSC, MSC and ISC may have different levels of potential in their ability to exert an immunomodulatory or pro-regenerative effect. Combined cell therapies, such as co-transplantation of MSC and ISC, may provide improved therapeutic outcome compared to transplantation of a single cell population. Those cell-based therapies may not only improve the disease activity or tissue regeneration, but may also have the potential to decrease the risk of developing colitis-associated cancers.
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Affiliation(s)
- Ryuichi Okamoto
- a Center for Stem Cell and Regenerative Medicine , Tokyo Medical and Dental University , Tokyo , Japan
| | - Mamoru Watanabe
- b Department of Gastroenterology and Hepatology, Graduate School , Tokyo Medical and Dental University , Tokyo , Japan
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Hoornaert CJ, Luyckx E, Reekmans K, Dhainaut M, Guglielmetti C, Le Blon D, Dooley D, Fransen E, Daans J, Verbeeck L, Quarta A, De Vocht N, Lemmens E, Goossens H, Van der Linden A, Roobrouck VD, Verfaillie C, Hendrix S, Moser M, Berneman ZN, Ponsaerts P. In Vivo Interleukin-13-Primed Macrophages Contribute to Reduced Alloantigen-Specific T Cell Activation and Prolong Immunological Survival of Allogeneic Mesenchymal Stem Cell Implants. Stem Cells 2016; 34:1971-84. [PMID: 26992046 DOI: 10.1002/stem.2360] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 02/12/2016] [Indexed: 12/11/2022]
Abstract
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue-for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins-is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since "off-the-shelf" cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated macrophage phenotype in vivo and a reduced number of alloantigen-reactive IFNγ- and/or IL2-producing CD8(+) T cells compared to nonmodified allografts. Similarly, intracerebral IL13-expressing MSC allografts also exhibited prolonged survival and induction of an alternatively activated macrophage phenotype, although a peripheral T cell component was absent. In summary, this study demonstrates that both innate and adaptive immune responses are effectively modulated in vivo by locally secreted IL13, ultimately resulting in prolonged MSC allograft survival in both muscle and brain tissue. Stem Cells 2016;34:1971-1984.
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Affiliation(s)
- Chloé J Hoornaert
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Evi Luyckx
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Kristien Reekmans
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Maxime Dhainaut
- Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium
| | | | - Debbie Le Blon
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Dearbhaile Dooley
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Erik Fransen
- StatUa Centre for Statistics, University of Antwerp, Antwerp, Belgium
| | - Jasmijn Daans
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Louca Verbeeck
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Alessandra Quarta
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Nathalie De Vocht
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Evi Lemmens
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Herman Goossens
- Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | | | - Valerie D Roobrouck
- Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium
| | - Catherine Verfaillie
- Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium
| | - Sven Hendrix
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Muriel Moser
- Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium
| | - Zwi N Berneman
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
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Current therapies and investigational drugs for peripheral arterial disease. Hypertens Res 2015; 39:183-91. [PMID: 26631852 DOI: 10.1038/hr.2015.134] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 10/18/2015] [Accepted: 10/19/2015] [Indexed: 12/17/2022]
Abstract
Peripheral artery disease (PAD) is associated with elevated morbidity and mortality with cardiovascular (CV) disease. The guideline recommends smoking cessation and antiplatelet/antithrombotic drugs for asymptomatic and symptomatic PAD patients. It also recommends that PAD patients with critical limb ischemia (CLI) should be considered to receive endovascular and open surgical treatment for limb salvage. Although PAD patients with CLI receive these treatments, they are sometimes unable to deliver sufficient blood flow to eliminate their symptoms. Thus specific strategies are needed to promote enough blood flow. To establish the effective method, many investigations have been performed using cell-based therapy. Endothelial progenitor cells, mononuclear cells and mesenchymal stem cells have been well investigated in clinical settings. To induce angiogenesis, vascular endothelial growth factor, fibroblast growth factor and hepatocyte growth factor (HGF) have also been transfected in PAD patients. Among them, HGF is the most promising factor because it can induce angiogenesis without the induction of vascular inflammation and increased permeability. In this review article, we summarize current treatments and investigational drugs of PAD.
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Chen CL, Chou KJ, Fang HC, Hsu CY, Huang WC, Huang CW, Huang CK, Chen HY, Lee PT. Progenitor-like cells derived from mouse kidney protect against renal fibrosis in a remnant kidney model via decreased endothelial mesenchymal transition. Stem Cell Res Ther 2015; 6:239. [PMID: 26631265 PMCID: PMC4668678 DOI: 10.1186/s13287-015-0241-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 03/09/2015] [Accepted: 11/17/2015] [Indexed: 12/20/2022] Open
Abstract
Introduction Pathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD). Methods In this study, we established a CKD model by five-sixths nephrectomy and mouse kidney progenitor-like cells (MKPCs) were intravenously administered weekly for 5 weeks after establishing CKD. We examined the impact of MKPCs on the progression of renal fibrosis and the potential of MKPCs to preserve the angiogenic process and prevent endothelial mesenchymal transition in vivo and in vitro. Results Our results demonstrate that the MKPCs delayed interstitial fibrosis and the progression of glomerular sclerosis and ameliorated the decline of kidney function. At 17 weeks, the treated mice exhibited lower blood pressures, higher hematocrit levels, and larger kidney sizes than the control mice. In addition, the MKPC treatment prolonged the survival of the mice with chronic kidney injuries. We observed a decreased recruitment of macrophages and myofibroblasts in the interstitium and the increased tubular proliferation. Notably, MKPC both decreased the level of vascular rarefaction and prevented endothelial mesenchymal transition (EndoMT) in the remnant kidneys. Moreover, the conditioned medium from the MKPCs ameliorated endothelial cell death under hypoxic culture conditions and prevented TGF-β-induced EndoMT through downregulation of phosphorylated Smad 3 in vitro. Conclusions MKPCs may be a beneficial treatment for kidney diseases characterized by progressive renal fibrosis. The enhanced preservation of angiogenic processes following MKPC injections may be associated with decreased fibrosis in the remnant kidney. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell-based therapeutic strategies for regenerative medicine in renal fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0241-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- C L Chen
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - K J Chou
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - H C Fang
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - C Y Hsu
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - W C Huang
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - C W Huang
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - C K Huang
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - H Y Chen
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
| | - P T Lee
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, 386 Ta-Chung 1st Rd, Kaohsiung, 813, Taiwan.
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LU WEIFENG, SI YI, DING JIANYONG, CHEN XIAOLI, ZHANG XIANGMAN, DONG ZHIHUI, FU WEIGUO. Mesenchymal stem cells attenuate acute ischemia-reperfusion injury in a rat model. Exp Ther Med 2015; 10:2131-2137. [PMID: 26668605 PMCID: PMC4665152 DOI: 10.3892/etm.2015.2806] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 09/01/2015] [Indexed: 01/06/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) following lung transplantation is associated with increased pulmonary inflammatory responses during reperfusion. Mesenchymal stem cells (MSCs) may be able to modulate inflammatory responses in IRI. The aim of the present study was to evaluate the beneficial effects of an intravenous infusion of bone marrow-derived MSCs (BMSCs) in a rat model of pulmonary IRI. IRI was induced in male Lewis rats by 1-h ischemia followed by 2-h reperfusion. The rats received phosphate-buffered saline (PBS) or BMSC infusion at the onset of reperfusion. Pulmonary injury was determined based on the mean blood oxygenation, lung edema and vascular permeability, and performing histopathological examination. Pulmonary inflammation was also evaluated through the examination of the levels of inflammatory cytokines. Compared with the PBS infusion, the BMSC infusion significantly preserved lung function, reduced lung edema and pulmonary microvascular permeability, and decreased the total injury score in rats with IRI. The mRNA levels of the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were significantly reduced, while the expression of anti-inflammatory cytokine IL-10 was increased in the rats receiving BMSC infusion. The levels of cytokine-induced neutrophil chemoattractant-1, IL-1β, and TNF-α in bronchoalveolar lavage fluid were also markedly reduced following BMCS infusion. In conclusion, the present results suggested that BMSC infusion exerts protective effects against pulmonary IRI by alleviating IRI-induced inflammation. These findings provide experimental evidence for the treatment of pulmonary IRI using BMSC cell therapy.
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Affiliation(s)
- WEIFENG LU
- Department of Vascular Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - YI SI
- Department of Cardiovascular Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200032, P.R. China
| | - JIANYONG DING
- Department of Thoracic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - XIAOLI CHEN
- Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - XIANGMAN ZHANG
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - ZHIHUI DONG
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - WEIGUO FU
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
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Onishi R, Ohnishi S, Higashi R, Watari M, Yamahara K, Okubo N, Nakagawa K, Katsurada T, Suda G, Natsuizaka M, Takeda H, Sakamoto N. Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats. Cell Transplant 2015; 24:2601-14. [DOI: 10.3727/096368915x687570] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of human amnion-derived MSCs (AMSCs) in rats with severe colitis. Colitis was induced by the administration of 8% dextran sulfate sodium (DSS) from day 0 to day 5, and AMSCs (1 × 106 cells) were transplanted intravenously on day 1. Rats were sacrificed on day 5, and the colon length and histological colitis score were evaluated. The extent of inflammation was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The effect of AMSCs on the inflammatory signals was investigated in vitro. AMSC transplantation significantly ameliorated the disease activity index score, weight loss, colon shortening, and the histological colitis score. mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and migration inhibitory factor (MIF) were significantly decreased in the rectums of AMSC-treated rats. In addition, the infiltration of monocytes/macrophages was significantly decreased in AMSC-treated rats. In vitro experiments demonstrated that activation of proinflammatory signals induced by TNF-α or lipopolysaccharide (LPS) in immortalized murine macrophage cells (RAW264.7) was significantly attenuated by coculturing with AMSCs or by culturing with a conditioned medium obtained from AMSCs. Although the phosphorylation of IκB induced by TNF-α or LPS was not inhibited by the conditioned medium, nuclear translocation of NF-κB was significantly inhibited by the conditioned medium. Taken together, AMSC transplantation provided significant improvement in rats with severe colitis, possibly through the inhibition of monocyte/macrophage activity and through inhibition of NF-κB activation. AMSCs could be considered as a new cell source for the treatment of severe colitis.
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Affiliation(s)
- Reizo Onishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Ryosuke Higashi
- Laboratory of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Michiko Watari
- Department of Gynecology, Tenshi Hospital, Sapporo, Japan
| | - Kenichi Yamahara
- Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Naoto Okubo
- Laboratory of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Koji Nakagawa
- Laboratory of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Takehiko Katsurada
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroshi Takeda
- Laboratory of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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A discussion on adult mesenchymal stem cells for drug delivery: pros and cons. Ther Deliv 2015; 6:1335-46. [DOI: 10.4155/tde.15.80] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are emerging as candidates for drug delivery to treat numerous diseases. Their ease of isolation, expansion and reduced ethical concern, coupled with their ‘plastic’ immune functions and homing abilities make MSCs an appealing choice as cellular vehicle for drug delivery, including the delivery of RNA. However, while MSCs are currently listed for thousands of clinical trials, there are many confounding factors that have yet to be elucidated. In this review, we address many of the benefits of MSCs as therapeutic agents, and discuss confounding factors that require further scientific exploration.
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Ono M, Ohnishi S, Honda M, Ishikawa M, Hosono H, Onishi R, Nakagawa K, Takeda H, Sakamoto N. Effects of human amnion–derived mesenchymal stromal cell transplantation in rats with radiation proctitis. Cytotherapy 2015; 17:1545-59. [DOI: 10.1016/j.jcyt.2015.07.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 06/09/2015] [Accepted: 07/04/2015] [Indexed: 01/25/2023]
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Antoniadou E, David AL. Placental stem cells. Best Pract Res Clin Obstet Gynaecol 2015; 31:13-29. [PMID: 26547389 DOI: 10.1016/j.bpobgyn.2015.08.014] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 08/31/2015] [Indexed: 12/14/2022]
Abstract
The placenta represents a reservoir of progenitor, stem cells and epithelial cells that have been shown to differentiate into various types, including adipogenic, osteogenic, myogenic, hepatogenic, cardiac, pancreatic, endothelial, pulmonary and neurogenic lineages. This review focuses on the properties of placenta-derived cells, and it evaluates their current therapeutic applications in regenerative medicine and cell transplantations. Ongoing clinical and preclinical studies are investigating the safety and efficacy of the human amniotic epithelial cells (hAECs), human amniotic mesenchymal stromal cells (hAMSCs) and chorionic mesenchymal stromal cells (hCMSCs). The establishment of biobanks for placental stem cells will enable the translation of scientific research into the clinic. The advantage of the placenta as a cellular source is that it contains different cell lineages, such as the haematopoietic lineage that originates from the chorion, allantois and yolk sac, and the mesenchymal lineage that originates from the chorion and amnion. In this review, we address advances in placental stem cell characterization, and we explore their possible uses in cell therapy.
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Affiliation(s)
- Eleni Antoniadou
- Stem Cells and Regenerative Medicine Section, Developmental Biology and Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
| | - Anna L David
- Institute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UK.
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Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Liver Fibrosis in Rats. Transplant Direct 2015; 1:e16. [PMID: 27500218 DOI: 10.1097/txd.0000000000000525] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/24/2015] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of transplantation of human amnion-derived MSCs (hAMSCs) in rats with liver fibrosis. METHODS Liver fibrosis was induced by an intraperitoneal injection of 2 mL/kg of 50% carbon tetrachloride twice a week for 6 weeks. At 3 weeks, hAMSCs (1 × 10(6) cells) were transplanted intravenously. Rats were sacrificed at 7 weeks, and histological analyses and quantitative reverse-transcription polymerase chain reaction were performed. In vitro experiments were conducted to investigate the effect of hAMSCs on the activation of Kupffer cells. RESULTS Transplantation of hAMSCs significantly reduced the fibrotic area, deposition of type-I collagen, the number of α-smooth muscle actin-positive hepatic stellate cells, and CD68-positive Kupffer cells in the livers. messenger RNA expression of α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 was significantly decreased and the expression of matrix metalloproteinase-9 and hepatocyte growth factor was significantly increased in the liver of hAMSC-treated rats. Transplantation of hAMSCs at 3 weeks plus 5 weeks did not have an additive effect. In vitro experiments demonstrated that Kupffer cell activation induced by lipopolysaccharide was significantly decreased by culturing with conditioned medium obtained from hAMSCs. CONCLUSIONS Transplantation of hAMSCs provided significant improvement in a rat model of liver fibrosis, possibly through the inhibition of Kupffer cell and hepatic stellate cell activation. hAMSCs may be a potential new treatment for liver fibrosis.
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Oliveira MS, Barreto-Filho JB. Placental-derived stem cells: Culture, differentiation and challenges. World J Stem Cells 2015; 7:769-775. [PMID: 26029347 PMCID: PMC4444616 DOI: 10.4252/wjsc.v7.i4.769] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 12/17/2014] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
Stem cell therapy is a promising approach to clinical healing in several diseases. A great variety of tissues (bone marrow, adipose tissue, and placenta) are potentially sources of stem cells. Placenta-derived stem cells (p-SCs) are in between embryonic and mesenchymal stem cells, sharing characteristics with both, such as non-carcinogenic status and property to differentiate in all embryonic germ layers. Moreover, their use is not ethically restricted as fetal membranes are considered medical waste after birth. In this context, the present review will be focused on the biological properties, culture and potential cell therapy uses of placental-derived stem cells. Immunophenotype characterization, mainly for surface marker expression, and basic principles of p-SC isolation and culture (mechanical separation or enzymatic digestion of the tissues, the most used culture media, cell plating conditions) will be presented. In addition, some preclinical studies that were performed in different medical areas will be cited, focusing on neurological, liver, pancreatic, heart, muscle, pulmonary, and bone diseases and also in tissue engineering field. Finally, some challenges for stem cell therapy applications will be highlighted. The understanding of the mechanisms involved in the p-SCs differentiation and the achievement of pure cell populations (after differentiation) are key points that must be clarified before bringing the preclinical studies, performed at the bench, to the medical practice.
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Arutyunyan I, Elchaninov A, Fatkhudinov T, Makarov A, Kananykhina E, Usman N, Bolshakova G, Glinkina V, Goldshtein D, Sukhikh G. Elimination of allogeneic multipotent stromal cells by host macrophages in different models of regeneration. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:4469-4480. [PMID: 26191137 PMCID: PMC4503009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 04/26/2015] [Indexed: 02/07/2023]
Abstract
Allogeneic multipotent stromal cells were previously thought to be poorly recognized by host immune system; the prolonged survival in host environments was explained by their immune privileged status. As long as the concept is currently reconsidered, the routes of elimination of allogeneic multipotent stromal cells by host immunity must be taken into account. This is necessary for correct comprehension of their therapeutic action. The study was focused upon survival of umbilical cord-derived allogeneic multipotent stromal cells in different rat models of tissue regeneration induced by partial hepatectomy or by critical limb ischemia. The observations were carried out by means of vital labeling of the cells with PKH26 prior to injection, in combination with differential immunostaining of host macrophages with anti-CD68 antibody. According to the results, allogeneic multipotent stromal cells are specifically eliminated by host immune system; the efficacy can reach 100%. Massive clearance of transplanted cells by host macrophages is accompanied by appropriation of the label by the latter, and this is a pronounced case of misleading presentation of exogenous label by host cells. The study emphasizes the role of macrophages in host response and also the need of additional criteria for correct data interpretation.
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Affiliation(s)
- Irina Arutyunyan
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
| | - Andrey Elchaninov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of The Russian Federation1 Ostrovitianov Street, Moscow 117997, Russia
| | - Timur Fatkhudinov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of The Russian Federation1 Ostrovitianov Street, Moscow 117997, Russia
| | - Andrey Makarov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of The Russian Federation1 Ostrovitianov Street, Moscow 117997, Russia
| | - Evgeniya Kananykhina
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
| | - Natalia Usman
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of The Russian Federation1 Ostrovitianov Street, Moscow 117997, Russia
| | - Galina Bolshakova
- Scientific Research Institute of Human Morphology3 Tsurupa Street, Moscow 117418, Russia
| | - Valeria Glinkina
- Pirogov Russian National Research Medical University, Ministry of Healthcare of The Russian Federation1 Ostrovitianov Street, Moscow 117997, Russia
| | - Dmitry Goldshtein
- Research Centre of Medical Genetics1 Moskvorechie Street, Moscow 115478, Russia
| | - Gennady Sukhikh
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of The Russian Federation4 Oparina Street, Moscow 117997, Russia
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Kuchroo P, Dave V, Vijayan A, Viswanathan C, Ghosh D. Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway. Stem Cells Dev 2015; 24:437-50. [PMID: 25229480 PMCID: PMC4313407 DOI: 10.1089/scd.2014.0184] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 09/16/2014] [Indexed: 12/13/2022] Open
Abstract
Improvement in angiogenesis using mesenchymal stem cells (MSCs) is evolving as an option in patients with vascular insufficiencies. The paracrine factors secreted by MSCs have been attributed to the angiogenic response. This study was conducted to identify the factors secreted by umbilical cord-derived MSCs (UCMSCs) that might play a role in angiogenesis. To this aim, we evaluated the presence of well known proangiogenic factors in the conditioned media (CM) derived from UCMSCs by ELISA. While vascular endothelial growth factor (VEGF), a well known angiogenic factor, was not detected in the CM, gene expression was nevertheless detected in these cells. Further investigations revealed the presence of soluble VEGF receptors (sVEGF-R1 and R2) that were capable of neutralizing exogenous VEGF. Human umbilical cord vein-derived endothelial cells exposed in vitro to CM, in comparison to control media, showed improved migration (P<0.007) and capillary-like network formation (P<0.001) with no significant change in endothelial cell proliferation. The angiogenic response observed with the paracrine factors secreted by UCMSC could be due to the presence of significant levels of a metalloprotease and matrix metalloproteases-2 (237.4±47.1 ng/10(6) cells). Data suggest that a VEGF-independent pathway is involved in the angiogenic response observed with endothelial cells in the presence of UCMSC-CM.
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Affiliation(s)
- Pushpa Kuchroo
- Tissue Engineering Group, Regenerative Medicine, Reliance Life Sciences Pvt. Ltd. , Navi-Mumbai, Maharashtra, India
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44
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Sharma S, Bhonde R. Influence of Nuclear Blebs and Micronuclei Status on the Growth Kinetics of Human Mesenchymal Stem Cells. J Cell Physiol 2014; 230:657-66. [DOI: 10.1002/jcp.24789] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 08/29/2014] [Indexed: 12/13/2022]
Affiliation(s)
- Shikha Sharma
- School of Regenerative Medicine; Manipal University; Bangalore Karnataka India
| | - Ramesh Bhonde
- School of Regenerative Medicine; Manipal University; Bangalore Karnataka India
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Song Y, Wang Z, Wang Z, Zhang H, Li X, Chen B. Use of FK506 and bone marrow mesenchymal stem cells for rat hind limb allografts. Neural Regen Res 2014; 7:2681-8. [PMID: 25337114 PMCID: PMC4200736 DOI: 10.3969/j.issn.1673-5374.2012.34.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 11/29/2012] [Indexed: 01/08/2023] Open
Abstract
Dark Agouti rat donor hind limbs were orthotopically transplanted into Lewis rat recipients to verify the effects of bone marrow mesenchymal stem cells on neural regeneration and functional recovery of allotransplanted limbs in the microenvironment of immunotolerance. bone marrow mesenchymal stem cells were intramuscularly (gluteus maximus) injected with FK506 (tacrolimus) daily, and were transplanted to the injured nerves. Results indicated that the allograft group not receiving therapy showed severe rejection, with transplanted limbs detaching at 10 days after transplantation with complete necrosis. The number of myelinated axons and Schwann cells in the FK506 and FK506 + bone marrow mesenchymal stem cells groups were significantly increased. We observed a lesser degree of gastrocnemius muscle degeneration, and increased polymorphic fibers along with other pathological changes in the FK506 + bone marrow mesenchymal stem cells group. The FK506 + bone marrow mesenchymal stem cells group showed significantly better recovery than the autograft and FK506 groups. The results demonstrated that FK506 improved the immune microenvironment. FK506 combined with bone marrow mesenchymal stem cells significantly promoted sciatic nerve regeneration, and improved sensory recovery and motor function in hind limb allotransplant.
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Affiliation(s)
- Youxin Song
- Department of Orthopedics, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Zhujun Wang
- Department of Research, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Zhixue Wang
- Department of Anesthesia, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Hong Zhang
- Department of Surgery, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Xiaohui Li
- Department of Research, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Bin Chen
- Department of Orthopedics, Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
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Kim H, Han JW, Lee JY, Choi YJ, Sohn YD, Song M, Yoon YS. Diabetic Mesenchymal Stem Cells Are Ineffective for Improving Limb Ischemia Due to Their Impaired Angiogenic Capability. Cell Transplant 2014; 24:1571-84. [PMID: 25008576 DOI: 10.3727/096368914x682792] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The purpose of this study was to investigate the effects of diabetes on mesenchymal stem cells (MSCs) in terms of their angiogenic and therapeutic potential for repairing tissue ischemia. We culture-isolated MSCs from streptozotocin-induced diabetic rats (D-MSCs) and compared their proliferation, differentiation, and angiogenic effects with those from normal rats (N-MSCs). The angiogenic effects of MSCs were evaluated by real-time PCR, in vitro tube formation assay, and transplantation of the MSCs into a hindlimb ischemia model followed by laser Doppler perfusion imaging. The number of MSCs derived from diabetic rats was smaller, and their proliferation rate was slower than N-MSCs. Upon induction of differentiation, the osteogenic and angiogenic differentiation of D-MSCs were aberrant compared to N-MSCs. The expression of angiogenic factors was lower in D-MSCs than N-MSCs. D-MSCs cocultured with endothelial cells resulted in decreased tube formation compared to N-MSCs. D-MSCs were ineffective to improve hindlimb ischemia and showed lower capillary density and angiogenic gene expression in ischemic limbs than N-MSCs. D-MSCs have defective proliferation and angiogenic activities and are ineffective for repairing hindlimb ischemia. Newer measures are needed before MSCs can be employed as a source for autologous cell therapy.
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Affiliation(s)
- Hyongbum Kim
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
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Tachibana Y, Enmi JI, Agudelo CA, Iida H, Yamaoka T. Long-Term/Bioinert Labeling of Rat Mesenchymal Stem Cells with PVA-Gd Conjugates and MRI Monitoring of the Labeled Cell Survival after Intramuscular Transplantation. Bioconjug Chem 2014; 25:1243-51. [DOI: 10.1021/bc400463t] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Yoichi Tachibana
- Department of Biomedical Engineering and ‡Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Jun-ichiro Enmi
- Department of Biomedical Engineering and ‡Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Carlos A. Agudelo
- Department of Biomedical Engineering and ‡Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Hidehiro Iida
- Department of Biomedical Engineering and ‡Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Tetsuji Yamaoka
- Department of Biomedical Engineering and ‡Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Lv S, Cheng J, Sun A, Li J, Wang W, Guan G, Liu G, Su M. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting oxidative stress. Diabetes Res Clin Pract 2014; 104:143-54. [PMID: 24513119 DOI: 10.1016/j.diabres.2014.01.011] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 10/22/2013] [Accepted: 01/07/2014] [Indexed: 02/07/2023]
Abstract
AIMS Mesenchymal stem cells (MSCs) have been demonstrated to be protective in diabetic nephropathy (DN) by reducing albuminuria and attenuating glomerular injury. However, the mechanisms remain unclear. The aim of this study was to explore the effects of MSCs on oxidative stress in DN. MATERIALS/METHODS Streptozotocin-induced diabetic rats received no treatment or treatment with MSCs (2×10(6), via tail vein) for two continuous weeks. Two other control groups received the antioxidant-probucol or insulin. Eight weeks after treatment, physical, biochemical, renal functional and morphological parameters were measured. Glomerular mesangial cells were cultured for the in vitro experiment. RESULTS Green fluorescent protein-labeled MSCs were only detected around the glomeruli and near vessels in the kidney. MSCs treatment dramatically reduced blood glucose, urinary albumin excretion, creatinine clearance and renal mass index. The glomerulosclerosis as revealed by periodic acid Schiff staining and expression of collagen I and fibronectin was significantly reduced by MSC treatment. Oxidative stress was also markedly inhibited in the MSCs group. Furthermore, the expression of TGF-β and membrane localization of GLUT1 were also down-regulated by MSCs. MSCs secreted a significant amount of hepatocyte growth factor (HGF). In vitro, MSC conditioned medium inhibited up-regulation of TGF-β expression stimulated by high glucose and HGF neutralizing antibody blocked the inhibitory effect of MSC conditioned medium. CONCLUSIONS MSC treatment reduced urinary albumin excretion and ameliorated glomerulosclerosis. The mechanisms underlying these effects involved reduced blood glucose levels and cellular glucose uptake mediated by GLUT1, thus inhibiting oxidative stress.
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Affiliation(s)
- Shasha Lv
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Jing Cheng
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Aili Sun
- Department of Endocrinology, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Junhua Li
- Department of Laboratory, The People's Hospital of Ling County, Dezhou, Shandong, China
| | - Weiwei Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Guangju Guan
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
| | - Gang Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
| | - Moran Su
- Department of Pneumology, Shandong University Qilu Hospital, Jinan, Shandong, China
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Comparison of angiogenic, cytoprotective, and immunosuppressive properties of human amnion- and chorion-derived mesenchymal stem cells. PLoS One 2014; 9:e88319. [PMID: 24551087 PMCID: PMC3925106 DOI: 10.1371/journal.pone.0088319] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 01/06/2014] [Indexed: 01/14/2023] Open
Abstract
Although mesenchymal stem cells (MSCs) can be obtained from the fetal membrane (FM), little information is available regarding biological differences in MSCs derived from different layers of the FM or their therapeutic potential. Isolated MSCs from both amnion and chorion layers of FM showed similar morphological appearance, multipotency, and cell-surface antigen expression. Conditioned media obtained from amnion- and chorion-derived MSCs inhibited cell death caused by serum starvation or hypoxia in endothelial cells and cardiomyocytes. Amnion and chorion MSCs secreted significant amounts of angiogenic factors including HGF, IGF-1, VEGF, and bFGF, although differences in the cellular expression profile of these soluble factors were observed. Transplantation of human amnion or chorion MSCs significantly increased blood flow and capillary density in a murine hindlimb ischemia model. In addition, compared to human chorion MSCs, human amnion MSCs markedly reduced T-lymphocyte proliferation with the enhanced secretion of PGE2, and improved the pathological situation of a mouse model of acute graft-versus-host disease. Our results highlight that human amnion- and chorion-derived MSCs, which showed differences in their soluble factor secretion and angiogenic/immuno-suppressive function, could be ideal cell sources for regenerative medicine.
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Peng Y, Huang S, Wu Y, Cheng B, Nie X, Liu H, Ma K, Zhou J, Gao D, Feng C, Yang S, Fu X. Platelet rich plasma clot releasate preconditioning induced PI3K/AKT/NFκB signaling enhances survival and regenerative function of rat bone marrow mesenchymal stem cells in hostile microenvironments. Stem Cells Dev 2013; 22:3236-51. [PMID: 23885779 PMCID: PMC3868358 DOI: 10.1089/scd.2013.0064] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 07/25/2013] [Indexed: 01/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been optimal targets in the development of cell based therapies, but their limited availability and high death rate after transplantation remains a concern in clinical applications. This study describes novel effects of platelet rich clot releasate (PRCR) on rat bone marrow-derived MSCs (BM-MSCs), with the former driving a gene program, which can reduce apoptosis and promote the regenerative function of the latter in hostile microenvironments through enhancement of paracrine/autocrine factors. By using reverse transcription-polymerase chain reaction, immunofluorescence and western blot analyses, we showed that PRCR preconditioning could alleviate the apoptosis of BM-MSCs under stress conditions induced by hydrogen peroxide (H2O2) and serum deprivation by enhancing expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF) via stimulation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT/NF-κB signaling pathways. Furthermore, the effects of PRCR preconditioned GFP-BM-MSCs subcutaneously transplanted into rats 6 h after wound surgery were examined by histological and other tests from days 0-22 after transplantation. Engraftment of the PRCR preconditioned BM-MSCs not only significantly attenuated apoptosis and wound size but also improved epithelization and blood vessel regeneration of skin via regulation of the wound microenvironment. Thus, preconditioning with PRCR, which reprograms BM-MSCs to tolerate hostile microenvironments and enhance regenerative function by increasing levels of paracrine factors through PDGFR-α/PI3K/AKT/NF-κB signaling pathways would be a safe method for boosting the effectiveness of transplantation therapy in the clinic.
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Affiliation(s)
- Yan Peng
- The Key Laboratory of Trauma Treatment & Tissue Repair of Tropical Area, PLA, Department of Plastic Surgery, Guangzhou General Hospital of Guangzhou Command, Guangzhou, People's Republic of China
- Southern Medical University, Guangzhou, People's Republic of China
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Sha Huang
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, People's Republic of China
| | - Yan Wu
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, People's Republic of China
| | - Biao Cheng
- The Key Laboratory of Trauma Treatment & Tissue Repair of Tropical Area, PLA, Department of Plastic Surgery, Guangzhou General Hospital of Guangzhou Command, Guangzhou, People's Republic of China
| | - Xiaohu Nie
- Southern Medical University, Guangzhou, People's Republic of China
| | - Hongwei Liu
- Key Laboratory for Regenerative Medicine, Ministry of Education, Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Kui Ma
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Jiping Zhou
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Dongyun Gao
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Changjiang Feng
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Siming Yang
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Xiaobing Fu
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, People's Republic of China
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