Enhancement of Myocardial Regeneration Through Genetic Engineering of Cardiac Progenitor Cells Expressing Pim-1 Kinase

Fischer, Kimberlee M.; Cottage, Christopher T.; Wu, Wentao; Din, Shabana; Gude, Natalie; Avitabile, Daniele; Quijada, Pearl; Fransioli, Jenna; Sussman, Mark A.

doi:10.1161/circulationaha.109.884403

Cited by 193 publications

(233 citation statements)

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“…Stem cell therapy has recently been proposed as a promising strategy for cardiac repair after myocardial infarction (Mangi et al, 2003;Amado et al, 2005;Dai et al, 2005;Li et al, 2007;Xie et al, 2007;Cheng et al, 2008c;Fazel et al, 2008;Fischer et al, 2009). However, most ransplanted stem cells undergo apoptosis in the harsh microenvironment with poor blood and oxygen supply in the infarct zone (Haider and Ashraf, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of pro-survival molecules including Akt (Mangi et al, 2003), Pim-1 (Fischer et al, 2009), Bcl-2 (Li et al, 2007) and stem cell factor (SCF) (Fazel et al, 2008) prevented donor cells from apoptosis. At the same time, pharmacological preconditioning with growth factors and cytokines can also improve the survival of transplanted cells (Haider and Ashraf, 2008).…”

Section: Introductionmentioning

confidence: 99%

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SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

et al. 2011

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Bone marrow mesenchymal stem cells (MSCs) are considered as a promising cell source to treat the acute myocardial infarction. However, over 90% of the stem cells usually die in the first three days of transplantation. Survival potential, migration ability and paracrine capacity have been considered as the most important three factors for cell transplantation in the ischemic cardiac treatment. We hypothesized that stromal-derived factor-1 (SDF-1)/CXCR4 axis plays a critical role in the regulation of these processes. In this study, apoptosis was induced by exposure of MSCs to H 2 O 2 for 2 h. After re-oxygenation, the SDF-1 pretreated MSCs demonstrated a significant increase in survival and proliferation. SDF-1 pretreatment also enhanced the migration and increased the secretion of pro-survival and angiogenic cytokines including basic fibroblast growth factor and vascular endothelial growth factor. Western blot and RT-PCR demonstrated that SDF-1 pretreatment significantly activated the pro-survival Akt and Erk signaling pathways and up-regulated Bcl-2/Bax ratio. These protective effects were partially inhibited by AMD3100, an antagonist of CXCR4. We conclude that the SDF-1/CXCR4 axis is critical for MSC survival, migration and cytokine secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

et al. 2011

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“…The serine/threonine kinase Pim-1 is a critical downstream effector of Akt-mediated cardioprotective signaling (15)(16)(17)(18). Pim-1 is antiapoptotic and proproliferative, and recent findings indicate that it also exerts beneficial effects in part by preserving mitochondrial integrity (15).…”

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confidence: 99%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

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“…Thus molecular intervention strategies to enhance cardiac stem cell (CSC) proliferation and survival hold dramatic consequences for enhancing myogenesis and will empower therapeutically relevant implementation of myocardial regeneration. It was reported that genetically modified stem cells could repair infarcted myocardium, prevent remodeling, and nearly normalize cardiac performance (10,29). Two recent clinical trials on human studies suggest that intracoronary infusion of autologous CSCs or autologous cardiosphere-derived cells is effective in improving left ventricular (LV) systolic function and reducing infarct size in patients with heart failure (3, 28).…”

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confidence: 99%

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit ϩ CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit ϩ CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit ϩ CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit ϩ CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit ϩ CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit ϩ CSCs compared with MI hearts engrafted with control siRNA-treated c-kit ϩ CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFPinfected c-kit ϩ CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit ϩ CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit ϩ CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit ϩ CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.heart; HDAC4; regeneration; myocardial infarction; stem cells IT HAS NOW BEEN RECOGNIZED that adult hearts harbor distinct populations of cardiac progenitors (2,25,26,34), which have the potential to differentiate into cardiomyocytes, endothelia, and vascular smooth muscle cells. Furthermore, several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. Exponential advances in stem cell and regenerative biology are beginning to foster a transition toward therapeutic goals for cardiac regenerative medicine (8,14,15,33). However, poor cell viability, proliferation, and inefficient differentiation following transplantation have limited the reparative capacity of these cells in vivo (26,29,39). Thus molecular intervention strategies to enhance cardiac stem cell (CSC) proliferation and survival hold dramatic consequences for enhancing myogenesis and will empower therapeutically relevant implementation of myocardial regeneration. It was repor...

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Enhancement of Myocardial Regeneration Through Genetic Engineering of Cardiac Progenitor Cells Expressing Pim-1 Kinase

Cited by 193 publications

References 43 publications

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

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