Mitochondrial Function Controls Proliferation and Early Differentiation Potential of Embryonic Stem Cells

Mandal, Sudip; Lindgren, Anne; Srivastava, Anand; Clark, Amander T.; Banerjee, Utpal

doi:10.1002/stem.590

Cited by 285 publications

(251 citation statements)

References 38 publications

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“…This is in agreement with recent findings showing that mitochondrial OXPHOS is required for the proliferation of self-renewing hESCs [45,46]. On the other hand, iPSCs showed reduced levels of ATP reserve in comparison with hESCs.…”

Section: Discussionsupporting

confidence: 93%

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

et al. 2011

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Human induced pluripotent stem cells (iPSCs) have been recently found to harbor genomic alterations. However, the integrity of mitochondrial DNA (mtDNA) within reprogrammed cells has yet to be investigated. mtDNA mutations occur at a high rate and contribute to the pathology of a number of human disorders. Furthermore, the lack of mtDNA integrity may alter cellular bioenergetics and limit efficient differentiation. We demonstrated previously that the derivation of iPSCs is associated with mitochondrial remodeling and a metabolic switch towards glycolysis. Here, we have discovered that alterations of mtDNA can occur upon the induction of pluripotency. Massively parallel pyrosequencing of mtDNA revealed that human iPSCs derived from young healthy donors harbored single base mtDNA mutations (substitutions, insertions, and deletions), both homoplasmic (in all mtDNA molecules) and heteroplasmic (in a fraction of mtDNAs), not present in the parental cells. mtDNA modifications were mostly common variants and not disease related. Moreover, iPSC lines bearing different mtDNA mutational loads maintained a consistent human embryonic stem cell-like reprogramming of energy metabolism. This involved the upregulation of glycolytic enzymes, increased glucose-6-phosphate levels, and the over-expression of pyruvate dehydrogenase kinase 1 protein, which reroutes the bioenergetic flux toward glycolysis. Hence, mtDNA mutations within iPSCs may not necessarily impair the correct establishment of pluripotency and the associated metabolic reprogramming. Nonetheless, the occurrence of pathogenic mtDNA modifications might be an important aspect to monitor when characterizing iPSC lines. Finally, we speculate that this random rearrangement of mtDNA molecules might prove beneficial for the derivation of mutation-free iPSCs from patients with mtDNA disorders.

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Section: Discussionsupporting

confidence: 93%

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

et al. 2011

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“…Ample reports showed that the mitochondrial metabolism plays a pivotal role in stem cell proliferation and differentiation (Funes et al, 2007;Mandal et al, 2011;Xu et al, 2013). It is known that riboflavin and its cofactors are important components for mitochondrial metabolism (Hoppel and Tandler, 1975;Barile et al, 1997;Nelson and Cox, 2013).…”

Section: Discussionmentioning

confidence: 99%

Studies on organogenesis during regeneration in the earthworm, Eudrilus eugeniae, in support of symbiotic association with Bacillus endophyticus

Subramanian¹,

Sudalaimani²,

Christyraj³

et al. 2017

Turk J Biol

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Organogenesis and animal adaptation upon loss of body parts are crucial events in regeneration of all traits, and both are uncovered areas in biology. The organogenesis of the mouth and anus during regeneration was studied in Eudrilus eugeniae. It was found that the earthworm regenerates a functional mouth and anus in six days. During the course of organogenesis, the earthworm adopts unique starvation behavior for 5 days, and the starvation triggers the gut microflora of E. eugeniae to produce riboflavin. One of the efficient riboflavin-producing bacteria, Bacillus endophyticus, confirmed through 16S rRNA sequencing, has been isolated from its gut. The symbiotic association provides shelter and nutrition to the bacterium and the earthworm in return gets riboflavin to maintain homeostasis during the starvation period of early regeneration.

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“…Recently, more attention has been focused on mitochondria and cellular bioenergetics of stem cells, which has revealed their unique metabolic status [27][28][29]. It has been shown that mitochondrial activity or dormancy plays a major role in maintaining the undifferentiated state, whereas the proper activation and function of mitochondria is essential during the differentiation processes [29][30][31]. In addition, mitochondrial reactive oxygen species (ROS) regulate the differentiation of several stem cell types; and recently, ROS have been shown to inhibit adhesion of hMSCs to the site of injury [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Function and Energy Metabolism in Umbilical Cord Blood- and Bone Marrow-Derived Mesenchymal Stem Cells

Pietilä

Palomäki

Lehtonen

et al. 2012

Stem Cells and Development

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Human mesenchymal stem cells (hMSCs) are an attractive choice for a variety of cellular therapies. hMSCs can be isolated from many different tissues and possess unique mitochondrial properties that can be used to determine their differentiation potential. Mitochondrial properties may possibly be used as a quality measure of hMSC-based products. Accordingly, the present work focuses on the mitochondrial function of hMSCs from umbilical cord blood (UCBMSC) cells and bone marrow cells from donors younger than 18 years of age (BMMSC <18) and those more than 50 years of age (BMMSC >50). Changes of ultrastructure and energy metabolism during osteogenic differentiation in all hMSC types were studied in detail. Results show that despite similar surface antigen characteristics, the UCBMSCs had smaller cell surface area and possessed more abundant rough endoplasmic reticulum than BMMSC >50. BMMSC <18 were morphologically more UCBMSC-like. UCBMSC showed dramatically higher mitochondrial-to-cytoplasm area ratio and elevated superoxide and manganese superoxide dismutase (MnSOD) levels as compared with BMMSC >50 and BMMSC <18. All hMSCs types showed changes indicative of mitochondrial activation after 2 weeks of osteogenic differentiation, and the increase in mitochondrial-to-cytoplasm area ratio appears to be one of the first steps in the differentiation process. However, BMMSC >50 showed a lower level of mitochondrial maturation and differentiation capacity. UCBMSCs and BMMSCs also showed a different pattern of exocytosed proteins and glycoproteoglycansins. These results indicate that hMSCs with similar cell surface antigen expression have different mitochondrial and functional properties, suggesting different maturation levels and other significant biological variations of the hMSCs. Therefore, it appears that mitochondrial analysis presents useful characterization criteria for hMSCs intended for clinical use.

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Mitochondrial Function Controls Proliferation and Early Differentiation Potential of Embryonic Stem Cells

Cited by 285 publications

References 38 publications

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

Studies on organogenesis during regeneration in the earthworm, Eudrilus eugeniae, in support of symbiotic association with Bacillus endophyticus

Mitochondrial Function and Energy Metabolism in Umbilical Cord Blood- and Bone Marrow-Derived Mesenchymal Stem Cells

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