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Isolation of Perivascular Multipotent Precursor Cell Populations from Human Cardiac Tissue
Published on: October 8, 2016
Human pericytes for ischemic heart repair
Chien-Wen Chen1, Masaho Okada, Jonathan D Proto
1Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Insights
Human pericytes, derived from muscle, show therapeutic potential for heart attack recovery. Transplantation improved heart function and reduced damage by promoting blood vessel growth and reducing inflammation.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Cell Biology
Background:
- Human microvascular pericytes possess multipotent precursor capabilities for tissue repair, particularly in skeletal muscle.
- The therapeutic efficacy of pericytes in repairing ischemic heart disease remains largely unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of human skeletal muscle-derived pericytes for treating ischemic heart disease in a mouse model.
- To elucidate the mechanisms underlying pericyte-mediated cardiac repair, including paracrine effects and cellular interactions.
Main Methods:
- Purification of human pericytes from skeletal muscle and transplantation into acutely infarcted mouse hearts.
- Echocardiography to assess cardiac function, histological analysis for fibrosis and inflammation, and in vitro studies using pericyte-conditioned medium.
- Analysis of pericyte gene expression under normoxic and hypoxic conditions, and assessment of angiogenesis and microvascular support in vivo and in vitro.
Main Results:
- Pericyte transplantation significantly improved cardiac contractility and attenuated left ventricular dilatation compared to control groups.
- Pericyte treatment reduced myocardial fibrosis and inflammatory cell infiltration at the infarct site.
- Pericytes enhanced host angiogenesis, supported microvascular structures, and exhibited paracrine effects on fibroblasts and macrophages.
Conclusions:
- Intramyocardial transplantation of human pericytes promotes significant functional and structural recovery in ischemic heart disease.
- Pericyte-mediated cardiac repair involves a combination of paracrine signaling, immunomodulation, and pro-angiogenic effects.
- Pericytes demonstrate potential as a cell-based therapy for myocardial infarction, offering advantages over other progenitor cells.
Abstract:
Human microvascular pericytes (CD146(+)/34(-)/45(-)/56(-)) contain multipotent precursors and repair/regenerate defective tissues, notably skeletal muscle. However, their ability to repair the ischemic heart remains unknown. We investigated the therapeutic potential of human pericytes, purified from skeletal muscle, for treating ischemic heart disease and mediating associated repair mechanisms in mice. Echocardiography revealed that pericyte transplantation attenuated left ventricular dilatation and significantly improved cardiac contractility, superior to CD56+ myogenic progenitor transplantation, in acutely infarcted mouse hearts. Pericyte treatment substantially reduced myocardial fibrosis and significantly diminished infiltration of host inflammatory cells at the infarct site. Hypoxic pericyte-conditioned medium suppressed murine fibroblast proliferation and inhibited macrophage proliferation in vitro. High expression by pericytes of immunoregulatory molecules, including interleukin-6, leukemia inhibitory factor, cyclooxygenase-2, and heme oxygenase-1, was sustained under hypoxia, except for monocyte chemotactic protein-1. Host angiogenesis was significantly increased. Pericytes supported microvascular structures in vivo and formed capillary-like networks with/without endothelial cells in three-dimensional cocultures. Under hypoxia, pericytes dramatically increased expression of vascular endothelial growth factor-A, platelet-derived growth factor-β, transforming growth factor-β1 and corresponding receptors while expression of basic fibroblast growth factor, hepatocyte growth factor, epidermal growth factor, and angiopoietin-1 was repressed. The capacity of pericytes to differentiate into and/or fuse with cardiac cells was revealed by green fluorescence protein labeling, although to a minor extent. In conclusion, intramyocardial transplantation of purified human pericytes promotes functional and structural recovery, attributable to multiple mechanisms involving paracrine effects and cellular interactions.
