Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential

Luchsinger, Larry L.; Almeida, Mariana Justino de; Corrigan, David J.; Mumau, Melanie; Snoeck, Hans-Willem

doi:10.1038/nature16500

Cited by 211 publications

(176 citation statements)

References 35 publications

(46 reference statements)

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“…Consistently, miR-106b targeted the 30 untranslated regions (30 UTRs) of Mfn2, and Mfn2 proteins were abundant at the post-transcriptional level so that miR-214 could regulate Mfn2 gene at the posttranscriptional level [15, 32]. Previous studies have shown that miR-214 was overexpressed in MSCs of mice, but the expression of Mfn2 was lower in hematopoietic stem cells [9, 33]. In addition, adult bone marrow (BM)-derived stem cells were generated from HSCs and MSCs represented an important cell source for damaged tissue repair, indicating that the expression of Mfn2 decreases in rADMSCs [34].…”

Section: Discussionmentioning

confidence: 98%

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

Wu¹,

Jiang²,

Chen³

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study investigated whether microRNA-214 (miR-214) targets mitofusin-2 (Mfn2) in the process of fibroblast differentiation of adipose-derived mesenchymal stem cells (ADMSCs) during pelvic floor dysfunction (PFD) in Sprague Dawley (SD) rats with birth trauma. Methods: The ADMSCs were isolated from 4-6 week male SD rats (n = 20) and were cultured and divided into the blank, miR-214 mimic negative control (NC), miR-214 mimic, miR-214 inhibitor NC, miR-214 inhibitor, empty vector, Mfn2 over-expression and miR-214 + Mfn2 over-expression groups. Fibroblast differentiation of ADMSCs was measured with immunocytochemistry and immunofluorescence methods. The expression of miR-214 and the mRNA and protein expression of Mfn2, FSP1, Collagen I, Collagen III, Elastin, LOX, Fibulin-5, PPAR-γ and Runx2 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. A dual-luciferase reporter assay was performed to confirm whether Mfn2 was the target gene of miR-214. Results: During ADMSC differentiation into fibroblasts, miR-214 expression was up-regulated, but the expression of Mfn2 was down-regulated. Fibroblast differentiation of ADMSCs was promoted in the miR-214 mimic group but was inhibited in the miR-214 inhibitor and Mfn2 over-expression groups. The expression of Mfn2 was decreased, but the expression of FSP1, Collagen I, Collagen III, Elastin, LOX, Fibulin-5, PPAR-γ or Runx2 was increased in the miR-214 mimic group; the miR-214 inhibitor group and Mfn2 over-expression group exhibited the opposite results. Mfn2 was the target gene of miR-214. Conclusions: The study provided strong evidence that miR-214 could promote fibroblast differentiation of ADMSCs by down-regulating Mfn2 to improve PFD in SD rats with birth trauma.

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Section: Discussionmentioning

confidence: 98%

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

Wu¹,

Jiang²,

Chen³

et al. 2017

Cell Physiol Biochem

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“…Mitofusin 2 (Mfn2) deficiency mainly affects lymphoid-but not myeloid-dominant HSCs in the HSC population. Mfn2 activity modulates calcium signaling and negatively regulates nuclear translocation of nuclear factor of activated T cells (Nfat) to sustain lymphoid potential [26].…”

Section: Role Of the Tca Cycle And Oxphos In Hsc Differentiationmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…Mitochondrial dynamics also affect cellular processes involved in stem cell pluripotency. mitochondria to the endoplasmic reticulum, thereby inhibiting nuclear factor of activated T cells (Nfat) transcriptional activity [89 ]. This mechanism is required for maintenance of hematopoietic stem cells with extensive lymphoid potential.…”

Section: Mitochondrial Fusion and Fissionmentioning

confidence: 99%

Mitochondrial functions in stem cells

Margineantu

Hockenbery

2016

Current Opinion in Genetics & Development

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Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential

Cited by 211 publications

References 35 publications

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Mitochondrial functions in stem cells

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