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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

ABSTRACT: BACKGROUND:The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES:This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS:Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS:Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS:ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

SUBMITTER: Natsumeda M

PROVIDER: S-EPMC5796680 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

Natsumeda Makoto M Florea Victoria V Rieger Angela C AC Tompkins Bryon A BA Banerjee Monisha N MN Golpanian Samuel S Fritsch Julia J Landin Ana Marie AM Kashikar Nilesh D ND Karantalis Vasileios V Loescher Viky Y VY Hatzistergos Kostas E KE Bagno Luiza L Sanina Cristina C Mushtaq Muzammil M Rodriguez Jose J Rosado Marcos M Wolf Ariel A Collon Kevin K Vincent Louis L Kanelidis Anthony J AJ Schulman Ivonne H IH Mitrani Raul R Heldman Alan W AW Balkan Wayne W Hare Joshua M JM

Journal of the American College of Cardiology 20171101 20

<h4>Background</h4>The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT).<h4>Objectives</h4>This study sought to test the hypothesis that ACCT synergistically pro ...[more]

PMID: 29145950

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Project description:BackgroundAlopecia affects millions of individuals globally, with hair loss becoming more common among young people. Various traditional Chinese medicines (TCM) have been used clinically for treating alopecia, however, the effective compounds and underlying mechanism are less known. We sought to investigate the effect of Alpinetin (AP), a compound extracted from Fabaceae and Zingiberaceae herbs, in hair regeneration.MethodsAnimal model for hair regeneration was mimicked by depilation in C57BL/6J mice. The mice were then topically treated with 3 mg/ml AP, minoxidil as positive control (PC), or solvent ethanol as vehicle control (VC) on the dorsal skin. Skin color changes which reflected the hair growth stages were monitored and pictured, along with H&E staining and hair shaft length measurement. RNA-seq analysis combined with immunofluorescence staining and qPCR analysis were used for mechanism study. Meanwhile, Gli1CreERT2; R26RtdTomato and Lgr5EGFP-CreERT2; R26RtdTomato transgenic mice were used to monitor the activation and proliferation of Gli1+ and Lgr5+ HFSCs after treatment. Furthermore, the toxicity of AP was tested in keratinocytes and fibroblasts from both human and mouse skin to assess the safety.ResultsWhen compared to minoxidil-treated and vehicle-treated control mice, topical application of AP promoted anagen initiation and delayed catagen entry, resulting in a longer anagen phase and hair shaft length. Mechanistically, RNA-seq analysis combined with immunofluorescence staining of Lef1 suggested that Lgr5+ HFSCs in lower bulge were activated by AP via Wnt signaling. Other HFSCs, including K15+, Lef1+, and Gli1+ cells, were also promoted into proliferating upon AP treatment. In addition, AP inhibited cleaved caspase 3-dependent apoptosis at the late anagen stage to postpone regression of hair follicles. More importantly, AP showed no cytotoxicity in keratinocytes and fibroblasts from both human and mouse skin.ConclusionThis study clarified the effect of AP in promoting hair regeneration by activating HFSCs via Wnt signaling. Our findings may contribute to the development of a new generation of pilatory that is more efficient and less cytotoxic for treating alopecia.

Project description:Heterogeneity of mesenchymal stem cells (MSCs) influences the cell therapy outcome and the application in tissue engineering. Also, the application of subpopulations of MSCs in cartilage regeneration remains poorly characterized. CD146+ MSCs are identified as the natural ancestors of MSCs and the expression of CD146 are indicative of greater pluripotency and self-renewal potential. Here, we sorted a CD146+ subpopulation from adipose-derived mesenchymal stem cells (ADSCs) for cartilage regeneration. Methods: CD146+ ADSCs were sorted using magnetic activated cell sorting (MACS). Cell surface markers, viability, apoptosis and proliferation were evaluated in vitro. The molecular signatures were analyzed by mRNA and protein expression profiling. By intra-articular injections of cells in a rat osteochondral defect model, we assessed the role of the specific subpopulation in cartilage microenvironment. Finally, CD146+ ADSCs were combined with articular cartilage extracellular matrix (ACECM) scaffold for long term (3, 6 months) cartilage repair. Results: The enriched CD146+ ADSCs showed a high expression of stem cell and pericyte markers, good viability, and immune characteristics to avoid allogeneic rejection. Gene and protein expression profiles revealed that the CD146+ ADSCs had different cellular functions especially in regulation inflammation. In a rat model, CD146+ ADSCs showed a better inflammation-modulating property in the early stage of intra-articular injections. Importantly, CD146+ ADSCs exhibited good biocompatibility with the ACECM scaffold and the CD146+ cell-scaffold composites produced less subcutaneous inflammation. The combination of CD146+ ADSCs with ACECM scaffold can promote better cartilage regeneration in the long term. Conclusion: Our data elucidated the function of the CD146+ ADSC subpopulation, established their role in promoting cartilage repair, and highlighted the significance of cell subpopulations as a novel therapeutic for cartilage regeneration.

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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

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