Mitophagy promotes the stemness of bone marrow-derived mesenchymal stem cells

Previous studies demonstrated that mitochondrial fission arguments the stemness of bone marrow-derived mesenchymal stem cells (BMSCs). Because mitophagy is critical in removing damaged or surplus mitochondrial fragments and maintaining mitochondrial integrity, the present study was undertaken to test the hypothesis that mitophagy is involved in mitochondrial fission-enhanced stemness of BMSCs. Primary cultures of rat BMSCs were treated with tyrphostin A9 (TA9, a potent inducer of mitochondrial fission) to increase mitochondrial fission, which was accompanied by enhanced mitophagy as defined by increased co-staining of MitoTracker Green for mitochondria and LysoTracker Deep Red for lysosomes, as well as the increased co-localization of autophagy markers (LC3B, P62) and mitochondrial marker (Tom20). A mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) was used to promote mitophagy, which was confirmed by an increased co-localization of mitochondrial and lysosome biomarkers. The argumentation of mitophagy was associated with enhanced stemness of BMSCs as defined by increased expression of stemness markers Oct4 and Sox2, and enhanced induction of BMSCs to adipocytes or osteocytes. Conversely, transfection of BMSCs with siRNA targeting mitophagy-essential genes Pink1/ Prkn led to diminished stemness of the stem cells, as defined by depressed stemness markers. Importantly, concomitant promotion of mitochondrial fission and inhibition of mitophagy suppressed the stemness of BMSCs. These results thus demonstrate that mitophagy is critically involved in mitochondrial fission promotion of the stemness of BMSCs.

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The secretome of bone marrow mesenchymal stem cells-conditioned media varies with time and drives a distinct effect on mature neurons and glial cells (primary cultures)

Journal of Tissue Engineering and Regenerative Medicine ◽

10.1002/term.365 ◽

2011 ◽

Vol 5 (8) ◽

pp. 668-672 ◽

Cited By ~ 41

Author(s):

C. A. Ribeiro ◽

A. J. Salgado ◽

J. S. Fraga ◽

N. A. Silva ◽

R. L. Reis ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Glial Cells ◽

Primary Cultures ◽

Conditioned Media ◽

Distinct Effect ◽

Marrow Mesenchymal Stem Cells ◽

Mature Neurons

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Functional properties of mesenchymal multipotent stromal stem cells obtained from bone marrow of patients with liver cirrhosis

Kazan medical journal ◽

10.17816/kmj2213 ◽

2014 ◽

Vol 95 (5) ◽

pp. 669-674

Author(s):

B A Agaev ◽

R M Agaev ◽

A G Popandopulo ◽

R E Dzhafarli

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Liver Cirrhosis ◽

Functional Properties ◽

Primary Cultures ◽

Small Cells ◽

Viral Etiology ◽

Phenotypic Properties ◽

Autologous Mesenchymal Stem Cells

Aim. To study of the functional properties of autologous mesenchymal multipotent stem cells in patients with cirrhosis of different etiologies. Methods. Studied were the functional and phenotypic properties of autologous mesenchymal stem cells derived from the bone marrow in 35 patients (26 men and 9 women) with cirrhosis of the liver at the age of 19-53 years. Among the patients studied viral etiology was diagnosed in 18 (51.4%), alcohol - in 13 (37.1%), autoimmune - in 4 (11.4%) patients with liver cirrhosis. Results. Autologous mesenchymal stem cells from all of the observed patients were able to divide. The highest yield and the doubling rate of cell populations were observed in patients with viral cirrhosis. Comparative morphometric study of primary cultures derived stem cells in patients with autoimmune and alcoholic hepatitis, showed the presence of relatively small cells (less than 20 microns), which make up about 30% of the total number of cells. At the same time, in bone marrow derived cell cultures of patients with viral etiology of the disease the number of small cells was 1.5 times greater which makes approximately 49% of the total cell population. The vast majority of cultured stem cells, regardless of the etiology of cirrhosis express specific for these cells «stromal» markers - CD73, CD90 and CD105. Autologous mesenchymal stem cells isolated from bone marrow of patients with alcoholic liver cirrhosis characterized by the most pronounced pro-inflammatory, immunoregulatory potential. Conclusion. Functional and phenotypic properties of autologous mesenchymal stem cells in various forms of cirrhosis are different which requires adequate cultivation and correction before their transplantation.

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The involvement of mitochondrial fission in maintenance of the stemness of bone marrow mesenchymal stem cells

Experimental Biology and Medicine ◽

10.1177/1535370218821063 ◽

2019 ◽

Vol 244 (1) ◽

pp. 64-72 ◽

Cited By ~ 4

Author(s):

Xiaorong Feng ◽

Wenjing Zhang ◽

Wen Yin ◽

Y James Kang

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Protein Level ◽

Mitochondrial Dynamics ◽

Adipogenic Differentiation ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Marrow Mesenchymal Stem Cells

Mitochondrial dynamics, a complicated cellular process consisting of mitochondrial fusion and fission, has been suggested to be involved in regulating the stemness of bone marrow mesenchymal stem cells (BMSCs). This study was undertaken to explore the relationship between mitochondrial dynamics and the maintenance of BMSCs’ stemness. Rat BMSCs were treated with fibroblast growth factor 2 (FGF2) and epithelial growth factor (EGF) to induce differentiation. Mitochondrial dynamics was determined by mitochondrial length observed by confocal microscope and DLP1 (a protein promoting mitochondrial fission), OPA1 (a protein promoting mitochondrial fusion) expression revealed by Western blotting analysis. BMSCs’ stemness was determined by flow cytometry and osteogenic/adipogenic differentiation ability. We found that in the process of BMSCs differentiation, mitochondrial length was increased, along with a decreased protein level of DLP1 and an increased protein level of OPA1 in the mitochondria, indicating a shift toward mitochondrial fusion in BMSCs during differentiation. Notably, when the mitochondrial fission was inhibited by Mdivi-1, the stemness marker, CD90, was deceased along with the reduction of DLP1 expression. Under the same condition, the potential of BMSCs to be induced into adipocytes or osteocytes was decreased. Correspondingly, when BMSCs were treated with tyrphostin A9, a reagent promoting mitochondrial fission by increasing DLP1, the stemness marker, CD54, was increased with an increased potential of BMSCs to be induced into adipocytes or osteocytes. Hence, our results demonstrated that mitochondrial fission contributed to the maintenance of BMSCs’ stemness. Impact statement How to maintain the stemness of bone marrow mesenchymal stem cells (BMSCs) in cultures is a long-standing question. The present study found that mitochondrial dynamics affects the stemness of BMSCs in cultures and the retaining of mitochondrial fission enhances the stemness of BMSCs. This work thus provides a novel insight into strategic approaches to maintain the stemness of BMSCs in cultures in relation to the clinical application of bone-marrow stem cells.

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