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C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways.

Vajravelu BN, Hong KU, Al-Maqtari T, Cao P, Keith MC, Wysoczynski M, Zhao J, Moore JB, Bolli R - PLoS ONE (2015)

Bottom Line: SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions.In addition, SCF significantly promoted CPC migration in vitro.These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.

ABSTRACT
A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.

No MeSH data available.


Related in: MedlinePlus

The effect of c-kit activation on cardiac differentiation of CPCs.Murine c-kit+ CPCs were induced to differentiate in dexamethasone-containing media as described in Materials and Methods. Cells in the first two groups were incubated in serum reduced media without dexamethasone and treated either with (SCF) or without (Control) SCF. The latter two groups were treated with 10 nM dexamethasone in the presence (Dex+SCF) or absence (Dex) of SCF. The mRNA levels of indicated cardiac markers were assessed by qPCR. *, p<0.05 compared to the Control. †, p<0.05 compared to the Dex only treatment group.
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pone.0140798.g006: The effect of c-kit activation on cardiac differentiation of CPCs.Murine c-kit+ CPCs were induced to differentiate in dexamethasone-containing media as described in Materials and Methods. Cells in the first two groups were incubated in serum reduced media without dexamethasone and treated either with (SCF) or without (Control) SCF. The latter two groups were treated with 10 nM dexamethasone in the presence (Dex+SCF) or absence (Dex) of SCF. The mRNA levels of indicated cardiac markers were assessed by qPCR. *, p<0.05 compared to the Control. †, p<0.05 compared to the Dex only treatment group.

Mentions: Next, we tested if c-kit activity has any significant effect on the ability of CPCs to differentiate into cardiac lineages. For this, we subjected murine c-kit+ CPCs to a dexamethasone-induced differentiation protocol and co-treated the cells with or without SCF. Dexamethasone was able to mostly induce markers of myocytes in CPCs (Fig 6). Although, compared to the dexamethasone only treatment group, there was a significant decrease in the α-MHC mRNA level following SCF treatment, SCF failed to alter the overall gene expression profile in differentiating CPCs (Fig 6). This suggests that the c-kit/SCF axis does not play a significant role in cardiac differentiation of CPCs.


C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways.

Vajravelu BN, Hong KU, Al-Maqtari T, Cao P, Keith MC, Wysoczynski M, Zhao J, Moore JB, Bolli R - PLoS ONE (2015)

The effect of c-kit activation on cardiac differentiation of CPCs.Murine c-kit+ CPCs were induced to differentiate in dexamethasone-containing media as described in Materials and Methods. Cells in the first two groups were incubated in serum reduced media without dexamethasone and treated either with (SCF) or without (Control) SCF. The latter two groups were treated with 10 nM dexamethasone in the presence (Dex+SCF) or absence (Dex) of SCF. The mRNA levels of indicated cardiac markers were assessed by qPCR. *, p<0.05 compared to the Control. †, p<0.05 compared to the Dex only treatment group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608800&req=5

pone.0140798.g006: The effect of c-kit activation on cardiac differentiation of CPCs.Murine c-kit+ CPCs were induced to differentiate in dexamethasone-containing media as described in Materials and Methods. Cells in the first two groups were incubated in serum reduced media without dexamethasone and treated either with (SCF) or without (Control) SCF. The latter two groups were treated with 10 nM dexamethasone in the presence (Dex+SCF) or absence (Dex) of SCF. The mRNA levels of indicated cardiac markers were assessed by qPCR. *, p<0.05 compared to the Control. †, p<0.05 compared to the Dex only treatment group.
Mentions: Next, we tested if c-kit activity has any significant effect on the ability of CPCs to differentiate into cardiac lineages. For this, we subjected murine c-kit+ CPCs to a dexamethasone-induced differentiation protocol and co-treated the cells with or without SCF. Dexamethasone was able to mostly induce markers of myocytes in CPCs (Fig 6). Although, compared to the dexamethasone only treatment group, there was a significant decrease in the α-MHC mRNA level following SCF treatment, SCF failed to alter the overall gene expression profile in differentiating CPCs (Fig 6). This suggests that the c-kit/SCF axis does not play a significant role in cardiac differentiation of CPCs.

Bottom Line: SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions.In addition, SCF significantly promoted CPC migration in vitro.These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.

ABSTRACT
A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.

No MeSH data available.


Related in: MedlinePlus