Paracrine regulation in mesenchymal stem cells: the role of Rap1.

Abstract

Since the first report more than a decade ago that bone marrow (BM) stem cells transplantation could promote heart regeneration following myocardial infarction (MI),1 different types of stem cells have been examined. Among those investigated to date, mesenchymal stem cells (MSCs) have attracted huge interest owing to some of their unique properties that include easy isolation, high expandability and low immunogenicity. Nonetheless despite the promising results of animal studies and clinical trials, MSC-based therapy for MI still faces some fundamental hurdles.2 One of the major challenges is the poor cell engraftment and low cell-survival rate following transplantation caused by the hostile environment of the injured heart and change to the immunologic milieu of transplanted MSCs. In addition, the mechanisms of stem cell-mediated tissue repair are not fully understood. Low cell retention and poor myocardial differentiation cannot explain the remarkable recovery of heart function following MSCs treatment. Therefore, the paracrine effects of MSCs are currently thought to have a predominant role. Although many cytokines released from MSCs contribute to heart function recovery,3 some are useless and even harmful.4 Thus, there is an urgent need to optimize MSCs before their transplantation to improve cell survival and augment their paracrine effects. Recently, Rap1, a telomeric repeat binding factor 2 interacting protein 1, has been identified as an important modulator of the nuclear factor kappa-B (NF-κB) pathway.5, 6 This pathway has been reported to regulate MSCs secretion profiling and survival.7, 8 On the basis of these findings, modulation of the NF-κB pathway to mediate MSCs therapy is feasible and important. Nonetheless total deletion of NF-κB is lethal to cells.9 Identification of an important regulator that can mediate activity of the NF-κB pathway and subsequently regulate MSC therapeutic efficacy for MI is vital. The roles of Rap1 in regulation of MSCs and the underlying mechanisms have not been classified, thus to understand how Rap1 regulates the paracrine effects and cell survival of MSC-mediated heart repair following infarction by regulation of the NF-κB pathway, therefore, is important.10