The Potentiation of Mesenchymal Stem Cells Improves Cardiac Regeneration

Circulation Research, October 23, 2008

Mesenchymal stem cells (MSCs) are clinically attractive for a number of reasons which include, among other desirable qualities, their ease of intravenous administration, their ability to home-in on injured tissue, their proven ability to differentiate into a wide variety of tissue types, and their status as immune privileged "universal donor" cells, for which they are especially well known. Numerous clinical trials throughout the U.S. are currently in progress in which MSCs are intravenously administered to patients with a vast range of conditions, thereby validating MSCs as an already well-established and viable therapy. Especially in the treatment of myocardial infarction, allogeneic (in which the donor and recipient are different people) MSCs as a clinical therapy have yielded statistically significant benefits in cardiac patients.

Nevertheless, despite the already high level of success enjoyed by MSCs, scientists have been trying to improve the therapeutic efficacy of these highly potent adult stem cells even further. Now, through a process of molecular potentiation, a team of researchers has succeeded in attaining the goal.

Using MSCs which were modified to overexpress IGF-1, Dr. Husnain Haider and his colleagues at the University of Cincinnati in Ohio observed an overall improvement in cardiac regeneration which was associated with increased mobilization of endogenous bone marrow stem cells in an animal model of heart attack. The MSCs were transfected with this insulin-like growth factor gene, which previously has been found to play an important role in the efficacy of MSCs in a variety of therapeutic uses, including the reversal of kidney failure. Now Dr. Haider's study indicates that the IGF-1-transfected MSCs also possess superior efficacy in inhibiting pathological changes in rats following myocardial infarction, through the CXCR4 (a CXC chemokine receptor) signaling mechanism in the paracrine release of SDF-1-alpha (stromal-derived-factor being a chemotactically active molecule for lymphocytes), which promoted improved survival and engraftment by the MSCs in the infarcted cardiac tissue. Among other roles, CXCR4, also known as fusin, is specific for SDF-1 (also known as CXCL12) and has been identified in the homing ability of hematopoietic stem cells, and is already recognized as an important receptor in a wide variety of molecular processes.

Dr. Haider's results corroborate a recent study conducted by Dr. Kondo of Japan, in which angiogenesis from exogenously administered bone marrow stem cells in an animal model of critical limb ischemia was found to be highly dependent upon the moblization of endogenous bone marrow stem cells which were activated by the exogenous stem cells. Now Dr. Haider's group has observed that the ability of the exogenously administered MSCs to repair cardiac tissue and to inhibit further post-infarct pathological changes following a heart attack is also dependent upon the mobilization of endogenous bone marrow stem cells.

The role of IGF-1 in mobilizing endogenous bone marrow stem cells through paracrine activation of SDF-1-alpha/CXCR4 signaling, thereby increasing and improving the therapeutic efficacy of MSCs, is a discovery which may also prove to have additional applications in the potentiation of other types of stem cells.