Transplantation of Mesenchymal Cells Rejuvenated by the Overexpression of Telomerase and Myocardin Promotes Revascularization and Tissue Repair in a Murine Model of Hindlimb Ischemia

Madonna, Rosalinda; Taylor, Doris A.; Geng, Yong–Jian; Caterina, Raffaele De; Shelat, Harnath; Perin, Emerson C.; Willerson, James T.

doi:10.1161/circresaha.113.301690

Cited by 96 publications

(79 citation statements)

References 43 publications

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“…To date the molecular mechanisms of insulin resistance in diabetes have been explored extensively. Elevation of GLUT4 protein on cell membrane of peripheral insulin target tissues are responsible for improvement in senThis was consistent with the findings that ASC could transdifferentiate toward endothelial cells in vitro and release angiogenic factors such as VEGF, HGF, and vWF in vivo [33,34]. We thus concluded that ASC could restore islet function by reducing the apoptosis of islet cells and promoting islet vascularization.…”

Section: Discussionsupporting

confidence: 89%

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

Chen

et al. 2015

Endocr J

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Type 2 diabeTes melliTus (T2DM) accounts for more than 90% of all diabetic patients and is characterized by insulin resistance, hyperglycemia, systemic low-grade inflammation, and relative lack of insulin. Most T2DM patients experience β-cell exhaustion several years after diagnosis, and thus have to accept insulin therapy. However, insulin therapy is inconvenient for patients and does not completely prevent the development of diabetic complications. Stem cells are an attractive option to ameliorate diabetes for its abundant source and potential to acquire glucose-dependent insulin secretory function. Adult stem cells are an especially good candidate for its safety in terms of tumorigenicity and ethical concerns.Adipose-derived stem cells (ASC) have been stud- The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet β cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1β in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet β cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

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Section: Discussionsupporting

confidence: 89%

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

Chen

et al. 2015

Endocr J

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“…7 Analogous to previous reports, 9,10,12,49-51 we observed that the transplanted ASCs were incorporated in the vessels (RFP + /PCNA + / CD31 + ) in ischemic hindlimbs of mice, implying that some ASCs can differentiate into ECs in vivo. Moreover, the transplanted ASCs may also differentiate into vascular smooth muscle cells 52,53 and even pericyte-like cells in vivo 14 to stabilize the neovasculature and exert proangiogenic paracrine effects as well. [54][55][56] Indeed, both TP-KO ASC (RFP + /PCNA + / CD31 + ) and recipient-cell-derived (RFP -/PCNA + /CD31 + ) neovascularization were more than doubled than that in hindlimbs transplanted with WT ASCs, indicating enhanced differentiation toward ECs and paracine activity in TP-KO ASCs.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Shen

Zuo

Wang

et al. 2016

Circulation Research

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Rationale: Autologous adipose-derived stromal cells (ASCs) offer great promise as angiogenic cell therapy for ischemic diseases. Because of their limited self-renewal capacity and pluripotentiality, the therapeutic efficacy of ASCs is still relatively low. Thromboxane has been shown to play an important role in the maintenance of vascular homeostasis. However, little is known about the effects of thromboxane on ASC-mediated angiogenesis. Objective: To explore the role of the thromboxane-prostanoid receptor (TP) in mediating the angiogenic capacity of ASCs in vivo. Methods and Results: ASCs were prepared from mouse epididymal fat pads and induced to differentiate into endothelial cells (ECs) by vascular endothelial growth factor. Cyclooxygenase-2 expression, thromboxane production, and TP expression were upregulated in ASCs on vascular endothelial growth factor treatment. Genetic deletion or pharmacological inhibition of TP in mouse or human ASCs accelerated EC differentiation and increased tube formation in vitro, enhanced angiogenesis in in vivo Matrigel plugs and ischemic mouse hindlimbs. TP deficiency resulted in a significant cellular accumulation of β-catenin by suppression of calpain-mediated degradation in ASCs. Knockdown of β-catenin completely abrogated the enhanced EC differentiation of TP-deficient ASCs, whereas inhibition of calpain reversed the suppressed angiogenic capacity of TP re-expressed ASCs. Moreover, TP was coupled with Gαq to induce calpain-mediated suppression of β-catenin signaling through calcium influx in ASCs. Conclusion: Thromboxane restrained EC differentiation of ASCs through TP-mediated repression of the calpain-dependent β-catenin signaling pathway. These results indicate that TP inhibition could be a promising strategy for therapy utilizing ASCs in the treatment of ischemic diseases.

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“…Adipose tissue-mesenchymal stem cells (AT-MSCs) that coexpress telomerase reverse transcriptase and MYOCD show increased levels of endogenous octamer-binding transcription factor 4, myocyte-specific enhancer factor 2c, and homeobox protein NKX2-5, and exhibit high cardiovascular regenerative potential. 109,110 These cells also show decreased frequencies of both spontaneous cell death and Fas-induced apoptosis. 109 The delivery of the telomerase reverse transcriptase and MYOCD genes into AT-MSCs was shown to restore MSCs from aged mice by increasing cell survival, proliferation, and smooth muscle myogenic differentiation in vitro.…”

Section: Rejuvenation Of Cardiac Stem Cellsmentioning

confidence: 97%

Recent Developments in Cardiovascular Stem Cells

Madonna

Ferdinándy

Caterina

et al. 2014

Circulation Research

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45Human embryonic stem cells have been shown to differentiate to beating cardiomyocytes, SA nodal-like cells and mesodermal Recent Developments in Cardiovascular Research:The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields. It is our hope and expectation that these "Recent Development" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research-The Editors. 50 Moreover, the use of induced pluripotent stem cell-derived cardiac myocytes for cardiac repair is hampered by their immature phenotype and the presence of epigenetic and genetic changes.24,51,52 Resident and bone marrow cells and cortical bone-derived cells are considered as potential sources for differentiation to cardiac myocytes but lacking compelling evidence for cardiac myogenesis and perhaps exerting their salutary biological effects through paracrine mechanisms. 19,29,[53][54][55][56][57][58] Equally exciting and challenging are the discovery and characterization of other CPCs that could give raise to various cardiac cells types, including smooth muscle cells, endothelial cells, and fibroblasts. [59][60][61][62][63] An important problem to overcome is the multiple comorbidities and their comedications of ischemic heart disease patients with heart failure that may affect cytoprotective signaling triggered by the different stem cell, as well as survival and differentiation properties of such stem cells in the injured tissue. [64][65][66] Clearly, the rapid face of discoveries is dazzling and a complete coverage of the recent developments in cardiovascular stem cells would be beyond the scope of this article. We regret that many valuable works were not covered in part or at all included in the present overview on Recent Developments. Clinical Trials In Human PatientsThe ClinicalTrials.gov lists >1000 clinical trials including >600 studies in the United States alone that tests effects of various stem cells in human patients (http://www.clinicaltrials. gov/). The list includes 71 including 38 active clinical trials in patients with heart failure using various stem cells, such as adipose-derived, mesenchymal, human embryonic, autologous CD133 + and CD34 + stem cells among the others.18,67-74Autologous skeletal myoblasts were probably the first cell type used to regenerate functional myocardium. It was tested initially in a rabbit model of myocardial cryoinjury, which showed incorporation of the injected myoblasts and improved myocardial performance. 75 Subsequent observational studies were followed by randomized clinical trials in human patients with heart failure injected with autologous skele...

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Transplantation of Mesenchymal Cells Rejuvenated by the Overexpression of Telomerase and Myocardin Promotes Revascularization and Tissue Repair in a Murine Model of Hindlimb Ischemia

Cited by 96 publications

References 43 publications

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Recent Developments in Cardiovascular Stem Cells

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