Restoration of cardiac function with progenitor cells.
The biological limitations to cardiac regenerative growth create a clinical need to promote more efficient cardiac repair. Experimental studies and early-phase clinical trials indicate that progenitor cells may be useful as a therapeutic tool to improve heart function after myocardial ischaemia. This paper will summarize experimental studies to determine (1) the mechanisms underlying progenitor cell homing to ischaemic tissue and (2) to define transcription factors involved in endothelial maturation of progenitor cells. Homing seems to be assisted by a proteolytic enzyme, cathepsin L, which degrades the extracellular matrix. In an in vitro assay, a cathepsin inhibitor prevented different progenitor cell populations from passing through a matrigel layer. In vivo, progenitor cells lacking cathepsin L had an impaired capacity to promote neovascularization in ischaemic mouse limbs compared with normal, wild-type cells. Differentiation of progenitor cells towards the endothelial phenotype involves a member of the homeobox gene family, HoxA9. HoxA9 regulates endothelial gene expression (eNOS, KDR, VE-cadherin). Moreover, HoxA9-deficient mice have a severe impairment of neovascularization capacity after ischaemia. In the second part of the paper, we describe clinical studies using bone marrow or the peripheral blood-derived cells for functional recovery of patients with acute and chronic heart failure (TOPCARE-AMI, TOPCARE-CHF). Whereas blood-derived and bone marrow-derived progenitor cells were equally effective in patients with acute myocardial infarction, bone marrow-derived cells were significantly better than blood-derived progenitor cells in patients with chronic ischaemic heart disease.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany.
Rössig
Lothar
L
Dimmeler
Stefanie
S
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002986:Clinical Trials as Topic; D006801:Humans; D007511:Ischemia / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors