Cardiac Progenitor Cell Cycling Stimulated by Pim-1 Kinase

Abstract

Rationale Cardioprotective effects of Pim-1 kinase have been previously reported but the underlying mechanistic basis may involve a combination of cellular and molecular mechanisms that remain unresolved. The elucidation of the mechanistic basis for Pim-1 mediated cardioprotection provides important insights for designing therapeutic interventional strategies to treat heart disease. Objective Effects of cardiac-specific Pim-1 kinase expression on the cardiac progenitor cell (CPC) population were examined to determine whether Pim-1 mediates beneficial effects through augmenting CPC activity. Methods and Results Transgenic mice created with cardiac-specific Pim-1 overexpression (Pim-wt) exhibit enhanced Pim-1 expression in both cardiomyocytes and CPCs, both of which show increased proliferative activity assessed using 5-bromodeoxyuridine (BrdU), Ki-67, and c-Myc relative to nontransgenic controls. However, the total number of CPCs was not increased in the Pim-wt hearts during normal postnatal growth or after infarction challenge. These results suggest that Pim-1 overexpression leads to asymmetric division resulting in maintenance of the CPC population. Localization and quantitation of cell fate determinants Numb and α-adaptin by confocal microscopy were used to assess frequency of asymmetric division in the CPC population. Polarization of Numb in mitotic phospho-histone positive cells demonstrates asymmetric division in 65% of the CPC population in hearts of Pim-wt mice versus 26% in nontransgenic hearts after infarction challenge. Similarly, Pim-wt hearts had fewer cells with uniform α-adaptin staining indicative of symmetrically dividing CPCs, with 36% of the CPCs versus 73% in nontransgenic sections. Conclusions These findings define a mechanistic basis for enhanced myocardial regeneration in transgenic mice overexpressing Pim-1 kinase.

Regenerating new heart with stem cells

“…The recognition that the adult heart harbors a compartment of multipotent c-kit-positive cardiac stem cells (CSCs) (15)(16)(17)(18)(19)(20)(21)(22)(23) and other progenitor cell classes (24)(25)(26)(27)(28)(29) capable of differentiating into cardiomyocytes and coronary vessels has raised the challenging question concerning their embryologic origin and role in cardiac cell turnover and regeneration. CSCs are stored in interstitial structures with the characteristics of stem cell niches and can divide symmetrically and asymmetrically, with the ability to self-renew and form a committed progeny (17,21,30).…”

Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation

“…In zebrafish, Numb is required for heart left-right asymmetric morphogenesis via regulation of Notch signaling (Niikura et al, 2006). In mice, Numb is reportedly expressed in adult cardiac progenitor cells and is asymmetrically distributed during progenitor asymmetric division (Cottage et al, 2010;Mishra et al, 2011). Additionally, we have shown that NFPs are essential for epicardial cells entering into myocardium (Wu et al, 2010).…”

Hypoxia Induces Myocardial Regeneration in Zebrafish

“…6,32-40 Furthermore, we were able to identify genes within the upregulated group that have a heart-associated function (the Table) such as thbs4b, jak2a, txnipa, pim1, slc4a1a, and cxcr4b. 39,[41][42][43][44][45] A number of proproliferative genes were also shown to be upregulated in the wild-type sample compared with the dnHIF1␣ sample (the Table). 46 -51 Although the positive aspects of dedifferentiation have not been intensely investigated, we were able to identify a couple of genes that have been linked to this phenomenon, namely jak2a and cxcr4b, albeit these are most commonly associated with cancer cell dedifferentiation.…”