Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, in Contrast to Adipose Tissue-Derived Stromal Cells, Efficiently Improve Heart Function in Murine Model of Myocardial Infarction

Stępniewski, Jacek; Tomczyk, Mateusz; Andrysiak, Kalina; Kraszewska, Izabela; Martyniak, Alicja; Langrzyk, Agnieszka; Kulik, Klaudia; Wiśniewska, Ewa; Jez, Mateusz; Florczyk-Soluch, Urszula; Polak, Katarzyna; Podkalicka, Paulina; Kachamakova‐Trojanowska, Neli; Józkowicz, Alicja; Jaźwa-Kusior, Agnieszka; Dulak, Józef

doi:10.3390/biomedicines8120578

Cited by 29 publications

(20 citation statements)

References 35 publications

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“…All hiPSCs lines in this study were generated with the use of Sendai vectors (CytoTune-iPS Sendai Reprogramming Kit, ThermoFisher Scientific, Waltham, MA, USA). Control hiPSCs (HPSI1013ikuxp_1 line) from male skin fibroblasts were obtained from The Human Induced Pluripotent Stem Cells Initiative’s collection ( , accessed on 9 January 2017) or were generated from peripheral blood mononuclear cells (PBMCs) isolated from a healthy volunteer as described by Stępniewski et al [ 30 ]. The DMD hiPSCs line was reprogrammed from fibroblasts derived from a DMD patient carrying a mutation in gene encoding dystrophin (deletion of DMD exon 45) purchased from the Coriell Institute for Medical Research.…”

Section: Methodsmentioning

confidence: 99%

Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

et al. 2021

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Duchenne muscular dystrophy (DMD), caused by a lack of functional dystrophin, is characterized by progressive muscle degeneration. Interestingly, dystrophin is also expressed in endothelial cells (ECs), and insufficient angiogenesis has already been hypothesized to contribute to DMD pathology, however, its status in mdx mice, a model of DMD, is still not fully clear. Our study aimed to reveal angiogenesis-related alterations in skeletal muscles of mdx mice compared to wild-type (WT) counterparts. By investigating 6- and 12-week-old mice, we sought to verify if those changes are age-dependent. We utilized a broad spectrum of methods ranging from gene expression analysis, flow cytometry, and immunofluorescence imaging to determine the level of angiogenic markers and to assess muscle blood vessel abundance. Finally, we implemented the hindlimb ischemia (HLI) model, more biologically relevant in the context of functional studies evaluating angiogenesis/arteriogenesis processes. We demonstrated that both 6- and 12-week-old dystrophic mice exhibited dysregulation of several angiogenic factors, including decreased vascular endothelial growth factor A (VEGF) in different muscle types. Nonetheless, in younger, 6-week-old mdx animals, neither the abundance of CD31+α-SMA+ double-positive blood vessels nor basal blood flow and its restoration after HLI was affected. In 12-week-old mdx mice, although a higher number of CD31+α-SMA+ double-positive blood vessels and an increased percentage of skeletal muscle ECs were found, the abundance of pericytes was diminished, and blood flow was reduced. Moreover, impeded perfusion recovery after HLI associated with a blunted inflammatory and regenerative response was evident in 12-week-old dystrophic mice. Hence, our results reinforce the hypothesis of age-dependent angiogenic dysfunction in dystrophic mice. In conclusion, we suggest that older mdx mice constitute an appropriate model for preclinical studies evaluating the effectiveness of vascular-based therapies aimed at the restoration of functional angiogenesis to mitigate DMD severity.

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Section: Methodsmentioning

confidence: 99%

Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

et al. 2021

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“…We added 10 µM ROCK inhibitor Y-27632 (Abcam, Cambridge, United Kingdom) to the culture medium for the first 24 h after passage. Differentiation towards cardiomyocytes was performed according to the published protocol [62,63]. Briefly, hiPSCs were seeded in Geltrex TM -coated 24-well plates and cultured in E8 until reaching 90% confluency.…”

Section: Differentiation Of Human Ipsc-derived Cardiomyocytesmentioning

confidence: 99%

Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin

Koczurkiewicz-Adamczyk

Klaś

Gunia‐Krzyżak

et al. 2021

IJMS

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Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic’s toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses—including hepatotoxicity, mutagenic potential, and interaction with the hERG channel—were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds’ activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.

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“…Several literatures provide abundant information that human adipocytes mesenchymal stem cells (h-AMSCs) is an attractive resource for therapeutics and have beneficial effects in regenerating injured cardiomyocytes due to their self-renewal ability and broad differentiation potential under physiological and pathological conditions. [1][2][3] Despite the impressive potential of the h-AMSC-based therapy, several obstacles (e.g., the difficulty of maintaining self-renewal and poor survival due to apoptosis and/or necrosis at the administration site) have been encountered. 4 Some studies suggest that more than 90% of transplanted stem cells, either intravenously, intramyocardially, and intracoronary delivery, have necrosis and apoptosis and only about 5% transplanted stem cells can survive up to 14 days in infarcted myocardium.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxic Preconditioning Promotes Survivals of Human Adipocyte Mesenchymal Stem Cell via Expression of Prosurvival and Proangiogenic Biomarkers

Suryawan

Pikir

Rantam

et al. 2021

Preprint

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BackgroundContributing factors for improved survival of human adipocytes mesenchymal stem cells (h-AMSCs) cultured through hypoxia preconditioning, in example apoptosis inhibition involving BCL2 and HSP27 expression, trigger signal expression (VEGF), SCF expression, OCT-4 expression, and CD44+ expression.ObjectiveTo explain the mechanism and role of hypoxic preconditioning and the optimal duration of hypoxic preconditioning exposure to improve survival of h-AMSCs so that could it could be used as a benchmark for h-AMSCs culture strategy before transplantation.MethodsThis study was an experimental laboratory explorative study (in vitro study) with hypoxic preconditioning in human-adipose mesenchymal stem cells (h-AMSCs) cultures. This research was conducted through 4 stages ;First, Isolation and h-AMSCs culture from adipose tissue of patient (human). Second is the characterization of h-AMSCs from adipose tissue by phenotype (Flowcytometry) through CD44+, CD90+ and CD45-expression before being pre-conditioned for hypoxic treatment. Third, the hypoxic preconditioning in h-AMSCs culture (in vitro) was performed with an oxygen concentration of 1% for 24, 48 and 72 hours. Fourth, observation of survival from h-AMSCs culture was tested on the role of CD44 +, VEGF, SCF, OCT-4, BCL2, HSP27 with Flowcytometry method and apoptotic inhibition by Tunnel Assay method.ResultsThe result of regression test showed that time difference had an effect on VEGF expression (p=0,000; β=−0,482) and hypoxia condition also influenced VEGF expression (p= 0,000; β=0,774). The result of path analysis showed that SCF had an effect on OCT-4 expression (p=0,000; β=0,985). The regression test results showed that time effects on HSP27 expression (p=0.000; β=0.398) and hypoxia precondition also affects HSP27 expression (p=0.000; β=0.847). Pathway analysis showed that BCL2 expression inhibited apoptosis (p=0.030; β=−0.442) and HSP27 expression also inhibited apoptosis (p=0,000; β=−0.487).ConclusionIn conclusion, hypoxic preconditioning of h-AMSC culture has proven to increase the expression of VEGF, SCF, OCT-4, and BCL2 and HSP27. This study demonstrated and explained the existence of a new mechanism of increased h-AMSC survival in cultures with hypoxic preconditioning (O2 1%) via VEGF, SCF, OCT-4, BCL2, and HSP 27. But CD 44+ did not play a role in the mechanism of survival improvement of human AMSC survival.

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Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, in Contrast to Adipose Tissue-Derived Stromal Cells, Efficiently Improve Heart Function in Murine Model of Myocardial Infarction

Cited by 29 publications

References 35 publications

Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin

Hypoxic Preconditioning Promotes Survivals of Human Adipocyte Mesenchymal Stem Cell via Expression of Prosurvival and Proangiogenic Biomarkers

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