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(Circulation Research. 2008;103:1204.)
© 2008 American Heart Association, Inc.

Reviews

Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy

Massimiliano Gnecchi^*, Zhiping Zhang^*, Aiguo Ni, Victor J. Dzau

From the Mandel Center for Hypertension Research (M.G., Z.Z., A.N., V.J.D.); and Cardiovascular Division (Z.Z., A.N., V.J.D.), Department of Medicine, Duke University Medical Center, Durham, NC; Division of Cardiology (M.G.), Laboratory of Experimental Cardiology–Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; and Department of Heart, Blood and Lung (M.G.), University of Pavia, Italy.

Correspondence to Victor J. Dzau, MD, Davison Building 106, Duke University Medical Center, Durham, NC 27710. E-mail victor.dzau{at}duke.edu

This Review is part of a thematic series on Cellular Therapy, which includes the following articles:

The Stem Cell Movement [2008;102:1155–1168]

Aging and Disease as Modifiers of Efficacy of Cell Therapy [2008;102:1319–1330]

Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy [2008;102:1471–1482]

Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells [2008;103:1058–1071]

Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy

Assessment and Optimization of Cell Engraftment after Transplantation

Stem Cell Homing to Sites of Injury

Regulatory Considerations in Cell Transplantation
Eduardo Marbán Editor

Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and the number of newly generated cardiomyocytes and vascular cells, either by transdifferentiation or cell fusion, appear too low to explain the significant cardiac improvement described. Accordingly, we and others have advanced an alternative hypothesis: the transplanted stem cells release soluble factors that, acting in a paracrine fashion, contribute to cardiac repair and regeneration. Indeed, cytokines and growth factors can induce cytoprotection and neovascularization. It has also been postulated that paracrine factors may mediate endogenous regeneration via activation of resident cardiac stem cells. Furthermore, cardiac remodeling, contractility, and metabolism may also be influenced in a paracrine fashion. This article reviews the potential paracrine mechanisms involved in adult stem cell signaling and therapy.

Key Words: adult stem cells • paracrine signaling • cytoprotection • neovascularization • regeneration

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