C-kit Cardiac Progenitor Cells Research Articles

Abstract 19364: C-Kit + Cardiac Progenitor Cells are Important in Cardiomyocytes Generation i n vivo in Response to Sfrp2

Introduction: Resident c-Kit + cardiac progenitor cells (CPCs) differentiation into cardiomyocytes in vivo is controversial. Using lineage tracing and gene ablation techniques we documented that the Wnt signaling modulator Sfrp2 substantially increased differentiation of c-Kit + CPCs into cardiomyocytes in post-MI heart and restored cardiac function. Methods: c-Kit-CreERT2/mTeG mice were used where the c-Kit promoter drives expression of a tamoxifen (TX)-inducible Cre. Upon TX treatment Cre-mediated recombination drives expression of eGFP exclusively in c-Kit cells. Mice were crossed with a Diphtheria toxin receptor (DT) strain to selectively ablate heart c-Kit cells. Mice were subjected to myocardial infarction. 2 days later, mice were injected with Sfrp2 (0.5 μg) or saline at the infarct border zone. Heart tissue was analyzed 2 months post-MI for eGFP expression and various markers by microscopy. Results: c-Kit-CreERT2/mTeG model was tested. eGFP expression had no effect on in vitro c-Kit CPC differentiation or proliferation. In TX treated mice, >90% of c-Kit+ cells were eGFP+. No eGFP+ c-Kit+ cells were seen in vehicle-only mice (N=6, p<0.001). c-Kit negative cells, such as cardiomyocytes, endothelial cells, and smooth muscle cells, did not express eGFP following TX treatment. In sham animals, eGFP was localized to small c-Kit+ cells. In the vehicle MI group eGFP+ cardiomyocytes were rare (0.08% in infarct border zone. N=8, P=0.005). In contrast, the number of eGFP+ cardiomyocytes was significantly higher in the Sfrp2 treated group (15% in infarct border zone, N=10, P=0.0002). Co-localization of eGFP with blood vessels (0.77%, N=10) was infrequent. Induction of c-Kit CPC differentiation into cardiomyocytes by Sfrp2 was associated with lower fibrosis (15%, N=10, P=0.01), higher LV mass (58mg, N=10, P=0.01) and increased ejection fraction (16%, N=10, P=0.02). DT treatment ablated c-Kit cells (>95% N=4, P=0.01). Sfrp2 induction of c-Kit differentiation to cardiomyocytes and functional improvements were completely ablated by DT. Conclusion: Using c-Kit lineage-tracing and genetic ablation we have identified that these cells are important in cardiomyocyte generation in vivo in response to Sfrp2 and improves cardiac function following MI.

C-kit cardiac progenitor cells: What is their potential?

The very interesting paper by Tallini et al. (1) confirms our suggestion [derived from the study (2) of cardiospheres' formation by cardiovascular precursors (CPs) isolated from the heart of embryonic, fetal, neonatal, and adult transgenic mice expressing GFP under the control of the c-kit promoter] that c-kit expression identifies in the heart CPs, differentiating into endothelial, cardiac, and smooth muscle cells. On the basis of results obtained in adult hearts after cryoablation, Tallini et al. suggest that c-kit expression is associated with fibrous and vascular infarct repair but not with de novo myogenesis from c-kit+ CPs. They conclude that the increased c-kit expression in differentiated cardiomyocytes, in the injury border zone, could be the result of c-kit reexpression in committed myocytes (1). However, Hsieh et al. (3), using a genetic fate pulse-labeling approach, strongly evidenced that CPs contribute to the replacement of adult mammalian cardiomyocytes after injury, although not significantly to their renewal during normal aging. Although this study did not address the origin of the progenitors, heart-resident CPs appear to be the most likely source (4). The relationship between the various resident CPs so far described and their role in normal cardiac homeostasis, as well as their response to injury and the potential contribution of cardiomyocyte de-differentiation, await clarification. The apparently conflicting results will require careful assessment of these multiple hypothesis including the possibility, recently suggested by Bergmann et al (5), of the potential cell cycle reentry by some cardiomyocytes to resume DNA synthesis and mitosis.