Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury

Siena, Sara Di; Gimmelli, Roberto; Nori, Stefania Lucia; Barbagallo, Federica; Campolo, Federica; Dolci, Susanna; Rossi, Pellegrino; Venneri, Mary Anna; Giannetta, Elisa; Gianfrilli, Daniele; Feigenbaum, Lionel; Lenzi, Andrea; Naro, Fabio; Cianflone, Eleonora; Mancuso, Teresa; Torella, Daniele; Isidori, Andrea M.; Pellegrini, Manuela

doi:10.1038/cddis.2016.205

Cited by 43 publications

(44 citation statements)

References 52 publications

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“…The ratio of these proteins to β-actin expression in experimental groups was shown and described in a, b, c sections endothelial regeneration, proliferation and differentiation of the heart cells. The binding of G-CSF to its receptors (G-CSFR) activates the JAK/STAT signaling pathways, Akt and BCL2 and inhibits BAX and caspase-3, and affects the BAX/BCL2 ratio (cell death index), and protects from myocytes by reducing and inhibiting apoptosis [41]. It was reported that the AMI-induced scar tissue area after G-CSF therapy was significantly reduced [42].…”

Section: Discussionmentioning

confidence: 99%

The effect of preconditioning with high-intensity training on tissue levels of G-CSF, its receptor and C-kit after an acute myocardial infarction in male rats

Ghanimati

Rajabi

Ramezani

et al. 2020

BMC Cardiovasc Disord

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Background: Exercise training is known as a practical way to increase cardioprotection against stress, and it seems that stem cell recruitment is one of its mechanisms. The purpose of the present study was to investigate the effect of preconditioning with High-intensity interval training (HIIT) on tissue levels of G-CSF, its receptor and C-Kit following acute myocardial infarction in male rats. Methods: Twenty Male Wistar rats were randomly divided into 4 groups of control, MI, HIIT, and HIIT+MI. Training groups performed 2 weeks of high intensity interval training in 4 sections. The first section consisted training in 3 days and 2 sessions in each day (4 × 2 min with 35-40 m/min and 3 × 2 min with 25-30 m/min between high intervals. The second part included 2 days of training (4 × 2 min with 40 to 45 m/min and 3 × 2 min with 28 to 32 m /min). The third part was performed in 3 days with one more repetition. The fourth section consisted 2 days of training and with one more repetition compared to section 3. For induction of myocardial infarction, subcutaneous injection of isoprenaline was used. CK, total CK, LDH, and troponin T were measured in serum and G-CSF, G-CSFR and C-Kit proteins were measured by the Western Blot method in the heart tissue. Results: The results of this study showed that enzymes of CK, total CK, LDH, troponin T had a significant increase in both MI and HIIT+MI groups compared to the other two groups (P < 0.001) and these indices in the MI group were significantly higher than the HIIT+MI group. Also, the results demonstrated that G-CSF, G-CSFR and C-Kit protein expression in the heart tissue significantly increased after MI. As well as, 2 weeks of HIIT training significantly increased G-CSF and C-kit in the training group compared to the control group, but the training caused that these proteins does not increase in HIIT+MI group as much as MI group. Conclusions: Along with other protective pathways, high intensity interval training can increase cardioprotection and decrease heart injuries through the increase in G-CSF, G-CSFR and C-kit level.

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Section: Discussionmentioning

confidence: 99%

The effect of preconditioning with high-intensity training on tissue levels of G-CSF, its receptor and C-kit after an acute myocardial infarction in male rats

Ghanimati

Rajabi

Ramezani

et al. 2020

BMC Cardiovasc Disord

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“…Nevertheless, questions remain about their physiological role and relevance in adult hearts. Recently, Di Siena et al (2016) showed that constitutive activation of c-Kit receptor is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury These results point towards a significant role of endogenous c-Kit + eCPCs in cardiac repair, homeostasis and survival.…”

Section: Potential Significancementioning

confidence: 99%

Calcium‐dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow‐derived mesenchymal stem cells

Vigneault

Naud

et al. 2018

The Journal of Physiology

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Endogenous c-Kit cardiac progenitor cells (eCPCs) and bone marrow (BM)-derived mesenchymal stem cells (MSCs) are being developed for cardiac regenerative therapy, but a better understanding of their physiology is needed. Here, we addressed the unknown functional role of ion channels in freshly isolated eCPCs and expanded BM-MSCs using patch-clamp, microfluorometry and confocal microscopy. Isolated c-Kit eCPCs were purified from dog hearts by immunomagnetic selection. Ion currents were barely detectable in freshly isolated c-Kit eCPCs with buffering of intracellular calcium (Ca ). Under conditions allowing free intracellular Ca , freshly isolated c-Kit eCPCs and ex vivo proliferated BM-MSCs showed prominent voltage-independent conductances that were sensitive to intermediate-conductance K -channel (KCa3.1 current, I ) blockers and corresponding gene (KCNN4)-expression knockdown. Depletion of Ca induced membrane-potential (V ) depolarization, while store-operated Ca entry (SOCE) hyperpolarized V in both cell types. The hyperpolarizing SOCE effect was substantially reduced by I or SOCE blockade (TRAM-34, 2-APB), and I blockade (TRAM-34) or KCNN4-knockdown decreased the Ca entry resulting from SOCE. I suppression reduced c-Kit eCPC and BM-MSC proliferation, while significantly altering the profile of cyclin expression. I was reduced in c-Kit eCPCs isolated from dogs with congestive heart failure (CHF), along with corresponding KCNN4 mRNA. Under perforated-patch conditions to maintain physiological [Ca ] , c-Kit eCPCs from CHF dogs had less negative resting membrane potentials (-58 ± 7 mV) versus c-Kit eCPCs from control dogs (-73 ± 3 mV, P < 0.05), along with slower proliferation. Our study suggests that Ca -induced increases in I are necessary to optimize membrane potential during the Ca entry that activates progenitor cell proliferation, and that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.

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“…The differences of induction levels between Kit and EGFP in the overexpression experiments might reflect either post‐transcriptional regulation mechanisms or the involvement of additional DNA‐binding sites present in the Kit locus not included in the p18 and p70 constructs. The latter hypothesis is supported by the evidence that regulatory regions that promote Kit expression in PGCs and in other stem cell types are spread over 200 kb upstream to Kit ORF , indicating a complex level of regulation of Kit transcription. In agreement with our results, ChIP seq data showing Sox2 occupancy has been reported in close association to Oct4, Nanog, and Tcf3 within ±8 kb from the TSS of the Kit locus , suggesting a possible involvement of a pluripotency circuitry in the regulation of this gene.…”

Section: Discussionmentioning

confidence: 86%

“…Generation of Kit‐KO, Kit‐EGFP, and Sox2 loxP/loxP mice have been previously described . Sox2 loxP/loxP were intercrossed with Rosa26Cre‐Ert2 mice (Jackson Laboratories, Ann Harbor, MI) to generate Sox2 loxP/loxP , Rosa26Cre‐Ert2 mice.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Kit Expression in Early Mouse Embryos and ES Cells

et al. 2019

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Kit is a growth factor receptor that regulates proliferation and/or survival of many embryonic and postnatal stem cell types. When mutated, it can induce malignant transformation of the host cells. To dissect the Kit role in the control of ESC pluripotency, we studied its expression during early mouse embryogenesis and during the process of ESC derivation from inner cell mass (ICM) cells. We followed the in vitro development of early mouse embryos obtained from transgenic mice carrying Kit promoter regions fused to EGFP (Kit-EGFP) and found that they initiate EGFP expression at morula stage. EGFP expression is then maintained in the blastocyst, within the ICM, and its levels increase when cultured in the presence of MAPK and GSK3β inhibitors (2i) plus LIF compared with the LIF-only condition. Kit-EGFP ESCs showed nonhomogeneous EGFP expression pattern when cultured in LIF condition, but they upregulated EGFP expression, as well as that of Sox2, Nanog, Prdm14, when shifted to 2i-LIF culture. Similarly, primordial germ cells (PGCs) in the process of embryonic germ cell (EGC) conversion showed enhanced EGFP expression in 2i-LIF. Kit expression was affected by manipulating Sox2 levels in ESCs. Chromatin immunoprecipitation experiments confirmed that Sox2 binds Kit regulatory regions containing Sox2 consensus sequences. Finally, Kit constitutive activation induced by the D814Y mutation increased ESC proliferation and cloning efficiency in vitro and in teratoma assays in vivo. Our results identify Kit as a pluripotency-responsive gene and suggest a role for Kit in the regulation of ESC proliferation. STEM CELLS 2019;37:332-344 SIGNIFICANCE STATEMENTBy exploiting transgenic mice carrying Kit different promoter regions fused to EGFP (Kit-EGFP) it was found that embryos initiate EGFP expression at morula stage. EGFP expression is then maintained in the blastocyst, within the ICM, and more importantly, its levels along with those of Kit increase in ground state culture conditions (MAPK and GSK3β inhibitors [2i] and LIF) compared with standard conditions (LIF only). Indeed, it was found that ESCs upregulated EGFP expression, as well as that of Sox2, Nanog, Prdm14 but not Oct4 in 2i-LIF, whereas they showed a nonhomogeneous EGFP expression pattern when cultured in LIF only condition. It was found that primordial germ cells, that share a similar transcriptional profile with ESCs, are sensitive to ground state culture conditions during the transition to EGC state. It was also found that Sox2 controls Kit and EGFP expression in ESCs. Finally, by producing a constitutive active Kit allele, it was found that mutant ESCs impaired early embryo development following their injection in host blastocyst and showed increased proliferation rate in vitro and in teratoma assays in vivo. The results show that Kit regulatory regions respond to ground state culture conditions and suggest a role of Kit in the regulation of ESC proliferation.

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Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury

Cited by 43 publications

References 52 publications

The effect of preconditioning with high-intensity training on tissue levels of G-CSF, its receptor and C-kit after an acute myocardial infarction in male rats

The effect of preconditioning with high-intensity training on tissue levels of G-CSF, its receptor and C-kit after an acute myocardial infarction in male rats

Calcium‐dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow‐derived mesenchymal stem cells

Regulation of Kit Expression in Early Mouse Embryos and ES Cells

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