Heterogeneity of Mitochondrial Potential as a Marker for Isolation of Pure Cardiomyoblast Population

Khryapenkova, T. G.; Plotnikov, Egor Y.; Korotetskaya, M. V.; Сухих, Г. Т.; Zorov, Dmitry B.

doi:10.1007/s10517-009-0327-3

Cited by 10 publications

(6 citation statements)

References 13 publications

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“…Terzic et al, have reported improved global cardiac function in iPS cell treated mice, however, without substantiating cardiogenesis in the infarcted mice heart with immunohistological evidence. 8 Given the tumorgenic nature of pluripotent stem cells, it is important to ensure that the transplantation of SiPS is free of undifferentiated cells 24 which are potential contributors of tumorgenicity of iPS cells 16 . Even the use of isogenic animals for transplantation of SiPS failed to curtail their teratogenic characteristics in the heart.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of Skeletal Myoblasts for Induction of Pluripotency for Tumor-Free Cardiomyogenesis in the Infarcted Heart

Ahmed

Haider

Buccini

et al. 2011

Circulation Research

102

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Rationale Skeletal myoblasts (SMs) with inherent myogenic properties are better candidates for reprogramming to pluripotency. Objective To reprogram SMs to pluripotency and show that reprogrammed SMs (SiPs) express embryonic gene and microRNA profiles and transplantation of predifferentiated cardiac progenitors reduce tumor formation. Methods and Results The pMXs vector containing mouse cDNAs for Yamanaka’s quartet of stemness factors were used for transduction of SMs purified from male Oct4-GFP+ transgenic mouse. Three weeks later, GFP+ colonies of SiPS were isolated and propagated in vitro. SiPS were positive for alkaline phosphatase, expressed SSEA1 and displayed a panel of embryonic stem (ES) cell specific pluripotency markers. Embryoid body formation yielded beating cardiomyocyte-like cells which expressed early and late cardiac specific markers. SiPS also had embryonic microRNA profile which was altered during their cardiomyogenic differentiation. Noticeable abrogation of let-7 family and significant upregulation of miR-200a–c and miR-290 to 295 was observed in SiPS and SiPS derived cardiomyocytes respectively. In vivo studies in an experimental model of acute myocardial infarction showed extensive survival of SiPS and SiPS derived cardiomyocytes in mouse heart after transplantation. Our results from 4-week studies in DMEM without cells (group-1), SMs (group-2), SiPS (group-3) and SiPS derived cardiomyocytes (group-4) showed extensive myogenic integration of the transplanted cells in group-4 with attenuated infarct size and improved cardiac function without tumorgenesis. Conclusions Successful reprogramming was achieved in SMs with ES cell-like microRNA profile. Given the tumorgenic nature of SiPS, their pre-differentiation into cardiomyocytes would be important for tumor-free cardiogenesis in the heart.

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Section: Discussionmentioning

confidence: 99%

Reprogramming of Skeletal Myoblasts for Induction of Pluripotency for Tumor-Free Cardiomyogenesis in the Infarcted Heart

Ahmed

Haider

Buccini

et al. 2011

Circulation Research

102

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“…In addition to neutropenia, the loss of TAZ function also causes cardiomyopathy in BTHS. In contrast to mature neutrophils that have very few mitochondria, both myeloid progenitor cells and cardiomyoblasts/cardiomyocytes depend heavily on mitochondria (49–52), which may explain why the loss of mitochondrial protein tafazzin has more severe effects on these specific tissues and results in neutropenia and cardiomyopathy in BTHS.…”

Section: Discussionmentioning

confidence: 99%

The cellular and molecular mechanisms for neutropenia in Barth syndrome

Makaryan

Kulik

Vaz

et al. 2011

European J of Haematology

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Barth syndrome (BTHS), a rare, X-linked, recessive disease characterized by neutropenia and cardiomyopathy. BTHS is caused by loss-of-function mutations of the tafazzin (TAZ) gene. We developed a model of BTHS by transfecting human HL60 myeloid progenitor cells with TAZ-specific shRNAs. Results demonstrate a significant down-regulation in TAZ expression, mimicking the effects of naturally-occurring truncation mutations in TAZ. Flow cytometry analyses of cells with TAZ-specific, but not scrambled, shRNAs demonstrate nearly two-fold increase in proportion of annexin-V positive cells and significantly increased dissipation of mitochondrial membrane potential as determined by DIOC6-staining. Transfection of TAZ specific shRNA had similar effects in U937 myeloid cells but not in lymphoid cell lines. Further studies in HL60 myeloid progenitor cells revealed aberrant release of cytochrome c from mitochondria and significantly elevated levels of activated caspase-3 in response to TAZ knock-down. Treatment with caspase-specific inhibitor zVAD-fmk resulted in substantially reduced apoptosis to near-normal levels. These data suggest that neutropenia in BTHS is attributable to increased dissipation of mitochondrial membrane potential, aberrant release of cytochrome c, activation of caspase-3 and accelerated apoptosis of myeloid progenitor cells, and that this defect can be partially restored in vitro by treatment with caspase-specific inhibitors.

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“…It should be noted that, in contrast to neutrophils with few if any mitochondria, human myeloid progenitor cells as well as cardiac cells depend heavily on mitochondria, which is why any abnormalities leading to mitochondrial dysfunction will have detrimental consequences for the normal function and survival of these cells leading to neutropenia and cardiomyopathy as opposed to other cells that are normal and do not depend on mitochondria (Fossati et al , ; Khryapenkova et al , ; van Raam et al , ; Kohlhaas et al , ; Makaryan et al , ). Similar to other neutropenic patients, G‐CSF treatment of BTHS patients increases the level of circulating neutrophils to near normal levels resulting in reduced frequency of infection episodes (Cox et al , ; Adwani et al , ).…”

Section: Cellular Models Of Bthsmentioning

confidence: 99%

Advances in the understanding of Barth syndrome

Aprikyan¹,

Khuchua

2013

Br J Haematol

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SummaryBarth syndrome (BTHS) is an X-linked autosomal recessive disorder characterized by neutropenia, cardiomyopathy and growth retardation. BTHS was first described as mitochondrial disease affecting neutrophils as well as cardiac and skeletal muscles. Patients with neutropenia may have extremely low levels of circulating neutrophils and suffer from recurring sometimes life-threatening bacterial infections. Sepsis is not infrequent, may occur unexpectedly in a patient with no history for pronounced bacterial infections and may lead to death. The reduced level of circulating neutrophils suggests either a reduced production of myeloid cells in the bone marrow and premature apoptosis or aberrant clearance of neutrophils in peripheral blood. The underlying molecular defects are truncation, deletion or substitution mutations in the TAZ gene that appear to result in loss-of-function of the gene product tafazzin. Molecular mechanisms triggering neutropenia and cardiomyopathy in BTHS remain largely unclear. The current review focusses on recent advances in the understanding of molecular and cellular bases of neutropenia in Barth syndrome and covers the functional implications of the TAZ mutations, experimental models for neutropenia, the specific cellular abnormalities triggered by loss of TAZ function and potential novel therapeutic strategies for restoring the normal phenotype.

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Heterogeneity of Mitochondrial Potential as a Marker for Isolation of Pure Cardiomyoblast Population

Cited by 10 publications

References 13 publications

Reprogramming of Skeletal Myoblasts for Induction of Pluripotency for Tumor-Free Cardiomyogenesis in the Infarcted Heart

Reprogramming of Skeletal Myoblasts for Induction of Pluripotency for Tumor-Free Cardiomyogenesis in the Infarcted Heart

The cellular and molecular mechanisms for neutropenia in Barth syndrome

Advances in the understanding of Barth syndrome

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