Molecular basis of functional myogenic specification ofBona Fidemultipotent adult cardiac stem cells

Abstract

Ischemic Heart Disease (IHD) remains the developed world's number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapies can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona-fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.

Substance P enhances the local activation of NK1R-expressing c-Kit+ cardiac progenitor cells in right atrium of ischemia/reperfusion-injured heart

“…We demonstrated that SP promoted the stem cell properties of NK 1 R-expressing c-Kit + GATA4 + Nkx2.5 + /CD45 -cTnI -CPCs, which in turn was associated with high expression of pluripotency genes. It is well known that c-Kit and GATA4 expression is necessary and su cient for cardiac recovery [2]. In the case of c-Kit-activated transgenic mice, activated c-Kit receptors can improve cardiac recovery after cryoinjury [2].…”

“…It is well known that c-Kit and GATA4 expression is necessary and su cient for cardiac recovery [2]. In the case of c-Kit-activated transgenic mice, activated c-Kit receptors can improve cardiac recovery after cryoinjury [2]. CD45c-Kit + isolated/cultured cardiac stem cells (CSCs) derived from the c-Kit-activated transgenic mice promote CSC activation and differentiation in vitro through Akt pathways [2].…”

“…In the case of c-Kit-activated transgenic mice, activated c-Kit receptors can improve cardiac recovery after cryoinjury [2]. CD45c-Kit + isolated/cultured cardiac stem cells (CSCs) derived from the c-Kit-activated transgenic mice promote CSC activation and differentiation in vitro through Akt pathways [2]. Furthermore, c-Kit + cardiac outgrowth cells transplanted into the damaged heart improve the LVEF and increase neovascularization [25].…”

“…The c-Kit + CPCs were xed with 4% paraformaldehyde. They were stained with standard IFS methods as previous described [2,16,19]. After nuclear DAPI or Hoechst 33342 staining, immunostained confocal images were acquired using an inverted Zeiss Axio Observer Z1 microscope with 405, 458, 488, 514, 561, and 633 nm laser lines.…”

“…In 2003, the existence of resident cardiac progenitor cells (CPCs), which express c-Kit, GATA4, and Isl-1 and do not express CD45, CD31, CD34, or tryptase, were identi ed in adult heart tissue [1,2,3]. The resident c-Kit + CPCs are known to be present in the atria, apex, and ventricle [1,2,3]. Most resident c-Kit + CPCs are quiescent in the healthy adult myocardium [2].…”