Priming with Ligands Secreted by Human Stromal Progenitor Cells Promotes Grafts of Cardiac Stem/Progenitor Cells After Myocardial Infarction

Iso, Yoshitaka; Rao, Krithika S.; Poole, Charla N.; Zaman, A.K.M. Tarikuz; Curril, Ingrid M.; Sobel, Burton E.; Kajstura, Jan; Anversa, Piero; Spees, Jeffrey L.

doi:10.1002/stem.1546

Cited by 27 publications

(17 citation statements)

References 46 publications

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“…9–11 In other studies, however, particularly in models of acute MI, the magnitude of CPC differentiation into adult myocytes has been reported to be substantial. 1, 4, 28 As a consequence of these discrepant results, two different schools of thought have emerged: one that asserts that the beneficial effects of CPCs are underlain by the differentiation of transplanted cells into new vascular cells and mature myocytes, 29, 30 and another that asserts that transplanted CPCs produce their salubrious effects via paracrine mechanisms because they do not differentiate into adult myocytes and most of them disappear shortly after adoptive transfer. 2, 3 …”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Tang

Rokosh

et al. 2016

Circulation Research

145

111

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Conclusions:The beneficial effects of CPCs on left ventricular remodeling and dysfunction are sustained for at least 1 year and thus are likely to be permanent. Because transplanted CPCs do not differentiate into mature myocytes, their major mechanism of action must involve paracrine actions. These paracrine mechanisms could be very prolonged because some CPCs engraft, proliferate, and persist at 1 year. This is the first report that transplantation of any cell type in the heart induces a proliferative response that lasts at least 1 year. A major limitation of all of the aforementioned studies, however, is that the follow-up after cell therapy was relatively short (4-6 weeks); consequently, the long-term (≥1 year) effects of CPCs on LV function and structure in experimental models of ischemic cardiomyopathy remain unknown. Similarly, the safety of CPC therapy remains uncertain because potential adverse effects, such as tumor formation, would not be expected to be evident within the 4-to 6-week follow-up of the studies performed to date; a longer time frame is needed to assess this possibility. For the same reason, the long-term fate of transplanted CPCs beyond the first 4 to 6 weeks is essentially unknown.Another fundamental issue that remains to be clarified is the mechanism(s) that underlies the beneficial effects of CPCs.2 Differentiation of transplanted CPCs into myocytes and vascular cells has been thought to play an important role 15 but, as alluded to above, in our previous studies in models of ischemic cardiomyopathy, we did not observe formation of adult myocytes from transplanted cells 9-14 ; however, because in all of these studies 9,11-14 animals were followed-up for only 4 to 5 weeks after cell therapy, the possibility that differentiation of transplanted CPCs into mature myocytes may occur at a later time cannot be ruled out. Because we did not observe any evidence of differentiation of exogenous CPCs, [9][10][11][12][13][14] we have proposed 3 that these cells produce their salubrious effects, at least in part, by activating the pool of endogenous CPCs; however, this possibility has not been substantiated.Thus, several fundamental issues remain to be addressed regarding CPC therapy. From a translational standpoint, before clinical implementation, it is important to assess the long-term safety of CPC therapy and establish, in a rigorous and wellcontrolled experimental model, whether the cardiac reparative benefits of CPC administration are transient or permanent. From a conceptual standpoint, understanding the mechanism of action of exogenous CPCs requires an effort to illuminate the long-term fate of the transplanted cells and to establish whether or not their salubrious effects are mediated by differentiation of the transplanted cells into mature cardiac myocytes.This study was undertaken to elucidate these issues. Specifically, using a well-characterized rat model 9 and a rigorous, blinded study design, we sought to determine i) whether the effects of CPCs on LV function and remodeling after MI ...

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Section: Discussionmentioning

confidence: 99%

Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Tang

Rokosh

et al. 2016

Circulation Research

145

111

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“…The janus kinase (JAK)/STAT pathway is also known to mediate cytoprotection [25,26]. As we and others have shown before, MSC-secreted factors are able to activate STAT3 in skeletal and cardiac myocytes as well as in cardiac progenitor cells [12,27,28,29]. However, STAT3 is not in every cell type a key mediator of the cytoprotective stem cell action [12].…”

Section: Discussionmentioning

confidence: 99%

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Bader

Brodarac

Klose

et al. 2014

Cell Physiol Biochem

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Background/Aims: Cell-based therapies may be useful for treating ischemic diseases, but the underlying mechanisms are incompletely understood. We investigated the impact of cord blood mesenchymal stromal cell (CBMSC)- or fibroblast (FB)-secreted factors on starved endothelial cells and determined the relevant intracellular signaling pathways. Methods: HUVECs were subjected to glucose/serum deprivation (GSD) in hypoxia or normoxia, in presence of CBMSC- or FB-conditioned medium (CM). Viability and proliferation were determined via WST-8 conversion and BrdU incorporation. Apoptosis was quantified by annexin V/ethidium homodimer-III staining, nuclear fragmentation and cell morphology. mRNA expression and protein phosphorylation were determined by real-time qPCR and western blot. Experiments were repeated in presence of small-molecule inhibitors. Results: The negative impact of GSD was most pronounced at 21% O₂. Here, medium of CBMSCs and FBs increased viability and proliferation and reduced apoptosis of HUVECs. This was associated with increased STAT3 and ERK1/2 phosphorylation and BCL-2 expression. Under STAT3 inhibition, the beneficial effect of CBMSC-CM on viability and BCL-2 expression was abolished. Conclusion: Factors released by CBMSCs protect endothelial cells from the deleterious impact of GSD by activation of the STAT3 survival pathway. However, this phenomenon is not CBMSC-specific and can be reproduced using juvenile fibroblasts.

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“…MI was induced in 30 male SD rats (250–300 g) as previously reported with a slight modification . Animals were anesthetized with tribromoethanol (Avertin, 300 mg/kg; Sigma) intraperitoneally for 1 time.…”

Section: Methodsmentioning

confidence: 99%

Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair

Zhang

Yang

Yan

et al. 2016

JAHA

190

161

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BackgroundExosomes derived from mesenchymal stem cells (MSCs) were proved to boost cell proliferation and angiogenic potency. We explored whether cardiac stem cells (CSCs) preconditioned with MSC exosomes could survive and function better in a myocardial infarction model.Methods and ResultsDiI‐labeled exosomes were internalized with CSCs. They stimulated proliferation, migration, and angiotube formation of CSCs in a dose‐dependent manner. In a rat myocardial infarction model, MSC exosome–preconditioned CSCs had significantly better survival, enhanced capillary density, reduced cardiac fibrosis, and restored long‐term cardiac function. MicroRNA profiling analysis revealed that a set of microRNAs were significantly changed in CSCs after MSC exosome treatment.ConclusionsPretreatment of CSCs with MSC exosomes provided a promising strategy to improve survival and angiogenic potency of CSCs.

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Priming with Ligands Secreted by Human Stromal Progenitor Cells Promotes Grafts of Cardiac Stem/Progenitor Cells After Myocardial Infarction

Cited by 27 publications

References 46 publications

Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair

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Priming with Ligands Secreted by Human Stromal Progenitor Cells Promotes Grafts of Cardiac Stem/Progenitor Cells After Myocardial Infarction

Cited by 27 publications

References 46 publications

Long-Term Outcome of Administration of c-kit POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Long-Term Outcome of Administration of c-kit POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair

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Product

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Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction

Long-Term Outcome of Administration of c-kit ^POS Cardiac Progenitor Cells After Acute Myocardial Infarction