Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Hnatiuk, Anna P.; Ong, Sang-Ging; Olea, Fernanda Daniela; Locatelli, Paola; Riegler, Johannes; Lee, Won Hee; Jen, Cheng Hao; Lorenzi, Andrea; Giménez, Carlos Sebastián; Laguens, Rubén M.; Wu, Joseph C.; Crottogini, Alberto J.

doi:10.1161/jaha.116.003714

Cited by 32 publications

(15 citation statements)

References 46 publications

(74 reference statements)

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“…Although the underlying mechanisms are complex and as of yet unresolved, the molecule HIF-1 α has attracted much attention for cardioprotection. Several reports have indicated that forced expression of HIF-1 α in transplanted stem cells significantly favors their biological functions in vivo 7 , 36 , 37 , highlighting an important role for HIF-1 α in stem cell transplantation after myocardial injury. We found that after hypoxia treatment, HIF-1 α , but not HIF-2 α , was most highly upregulated in CMs.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Wang

Ding

et al. 2018

Acta Pharmaceutica Sinica B

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Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury, but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes (CMs) for driving the differentiation of cardiac stem cells (CSCs). Forced hypoxia-inducible factor 1α (HIF-1α) expression and physical hypoxia (5% O2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor (PD98059), but not inhibitors of JNK (SP600125), Notch (DAPT), NF-κB (PTDC), JAK (AG490), or STAT3 (Stattic) suppressed hypoxia-induced Jagged1 protein expression in CMs. c-Kit+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI. Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU+/Nkx2.5+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation. Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling, and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Wang

Ding

et al. 2018

Acta Pharmaceutica Sinica B

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“…With Bcl-2, VEGF overexpression improves cell survival and paracrine effect of the cells [56]. To ensure the effect of hypoxic preconditioning, HIF-1α can be transduced to BM-MSCs and emulate the therapeutic effects without any exposure process [57]. Genetic modification of BM-MSCs aiming to increase prostaglandin I synthase (PGIS) gene expression more successfully protects damaged heart and restore cardiac function in MI mouse model [58].…”

Section: Genetic Manipulation Of Mscsmentioning

confidence: 99%

Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application

Lee

Kang

2020

Stem Cell Res Ther

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Mesenchymal stem cells (MSCs) have recently been considered a promising alternative treatment for diverse immune disorders due to their unique biomedical potentials including the immunomodulatory property and ability to promote tissue regeneration. However, despite many years of pre-clinical studies in the research field, results from clinical trials using these cells have been diverse and conflicting. This discrepancy is caused by several factors such as poor engraftment, low survival rate, and donor-dependent variation of the cells. Enhancement of consistency and efficacy of MSCs remains a challenge to overcome the current obstacles to MSC-based therapy and subsequently achieve an improved therapeutic outcome. In this review, we investigated function enhancement strategies by categorizing as preconditioning, genetic manipulation, usage of supportive materials, and co-administration with currently used drugs. Preconditioning prior to MSC application makes up a large proportion of improvement strategies and preconditioning reagents include bioactive substances (cytokines, growth factors, and innate immune receptor agonists), hypoxia, and modification in culture method. With the piled results from previous studies using each method, disease- or patient-specific therapy has become more important than ever. On the other hand, genetic manipulation targeting therapeutic-associated factors or co-administration of biocompatible materials has also arisen as other therapeutic strategies. Thus, we summarized several specialized tactics by analyzing up-to-date results in the field and proposed some promising enhancement methods to improve the clinical outcomes for MSC therapy.

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“…at the same time, a variety of myocardial protection mechanisms are involved. This includes the hypoxia inducible factor 1/hypoxia response element pathway (HiF-1/Hre) and the mitochondrial aTP-sensitive potassium channels (mitoK aTP channels) (8,9).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning

et al. 2020

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ischemic post-conditioning (iPo) and diazoxide post-conditioning (dPo) has been proven to reduce myocardial ischemia reperfusion injury (Miri); however, the mechanisms of iPo/dPo are still not clear. The present study aimed to investigate whether mitochondrial aTP-sensitive potassium channels (mitoK aTP) channels are activated by iPo/dPo, which may further activate the hypoxia inducible factor 1/hypoxic response element (HiF-1/Hre) pathway to mitigate Miri. using a langendorff perfusion device, healthy male (250-300 g) Sprague dawley rat hearts were randomly divided into the following groups. Group n was aerobically perfused with K-H solution for 120 min. Group ischaemia/reperfusion (i/r) was aerobically perfused for 20 min, then subjected to 40 min hypoxia plus 60 min reperfusion. Group iPo was treated like the i/r group, but with 10 sec of hypoxia plus 10 sec of reperfusion for six rounds before reperfusion. Group dPo was exposed to 50 µM diazoxide for 5 min before reperfusion and otherwise treated the same as group i/r. in groups iPo+5-hydroxydecanoic acid (5Hd), dPo+5Hd and i/r+5Hd, exposure to 100 µM 5Hd (a mitoK aTP channel specific blocker) for 5 min before reperfusion as described for groups iPo, dPo and i/r, respectively. in groups iPo+2-methoxyestradiol (2Me2), dPo+2Me2 and i/r+2Me2, exposure to 2 µM 2Me2 (a HiF-1α specific blocker) for 10 min before reperfusion as described for groups iPo, dPo and i/r respectively. cardiac hemodynamics, myocardial injury and the expression of HiF-1/Hre pathway [HiF-1α, heme oxygenase (Ho-1), inducible nitric oxide synthase (inoS) and vascular endothelial growth factor (VeGF)] were detected in each group. The infarct size and mitochondrial Flameng scores of groups IPO/DPO were significantly decreased compared with the i/r group (P<0.05), but the myocardial protective effects of iPo/dPo could be eliminated by 5Hd or 2Me2 (P<0.05). in addition, iPo/dPo could increase the mrna expression of HiF-1α and the downstream factors of the HiF-1/Hre pathway (the mrna and protein expression of Ho-1, inoS and VeGF; P<0.05). However, the myocardial protective effects and the activation the HiF-1/Hre pathway mediated by iPo/dPo could be eliminated by 5Hd or 2Me2 (P<0.05). Therefore, the activation of the HiF-1/Hre pathway by opening mitoK aTP channels may work with the mechanism of iPo/dPo in reducing Miri.

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Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Cited by 32 publications

References 46 publications

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning

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