Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6

AbstractMesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6−/−) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6−/−-BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6−/−-BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6−/−-BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

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GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Cells ◽

10.3390/cells10020225 ◽

2021 ◽

Vol 10 (2) ◽

pp. 225

Author(s):

Claire Racaud-Sultan ◽

Nathalie Vergnolle

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adult Stem Cells ◽

Glycogen Synthase ◽

Inflammatory Diseases ◽

Adult Stem Cell ◽

Leukemic Cells ◽

Cell Phenotype ◽

Epithelial Regeneration ◽

Cell Functions

In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

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Mesenchymal stem cell‐conditioned medium attenuates the retinal pathology in amyloid‐β‐induced rat model of Alzheimer's disease: Underlying mechanisms

Aging Cell ◽

10.1111/acel.13340 ◽

2021 ◽

Author(s):

Shu‐Chun Kuo ◽

Chung‐Ching Chio ◽

Chao‐Hung Yeh ◽

Jui‐Ti Ma ◽

Wen‐Pin Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Conditioned Medium ◽

Rat Model ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease ◽

Retinal Pathology ◽

Underlying Mechanisms ◽

Cell Conditioned Medium

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Article Commentary: Stem Cell Research in Cell Transplantation: An Analysis of Geopolitical Influence by Publications

Cell Transplantation ◽

10.3727/000000007783465190 ◽

2007 ◽

Vol 16 (8) ◽

pp. 867-873 ◽

Cited By ~ 5

Author(s):

David J. Eve ◽

Paul R. Sanberg

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Transplantation ◽

Adult Stem Cells ◽

Adult Stem Cell ◽

Therapeutic Area ◽

Fetal Stem Cells ◽

Major Player ◽

The Us ◽

Restricted Use

One of the fastest growing fields in researching treatments for neurodegenerative and other disorders is the use of stem cells. These cells are naturally occurring and can be obtained from three different stages of an organism's life: embryonic, fetal, and adult. In the US, political doctrine has restricted use of federal funds for stem cells, enhancing research towards an adult source. In order to determine how this legislation may be represented by the stem cell field, a retrospective analysis of stem cell articles published in the journal Cell Transplantation over a 2-year period was performed. Cell Transplantation is considered a translational journal from preclinical to clinical, so it was of interest to determine the publication outcome of stem cell articles 6 years after the US regulations. The distribution of the source of stem cells was found to be biased towards the adult stage, but relatively similar over the embryonic and fetal stages. The fetal stem cell reports were primarily neural in origin, whereas the adult stem cell ones were predominantly mesenchymal and used mainly in neural studies. The majority of stem cell studies published in Cell Transplantation were found to fall under the umbrella of neuroscience research. American scientists published the most articles using stem cells with a bias towards adult stem cells, supporting the effect of the legislation, whereas Europe was the leading continent with a bias towards embryonic and fetal stem cells, where research is “controlled” but not restricted. Japan was also a major player in the use of stem cells. Allogeneic transplants (where donor and recipient are the same species) were the most common transplants recorded, although the transplantation of human-derived stem cells into rodents was the most common specific transplantation performed. This demonstrates that the use of stem cells is an increasingly important field (with a doubling of papers between 2005 and 2006), which is likely to develop into a major therapeutic area over the next few decades and that funding restrictions can affect the type of research being performed.

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FGF21 Mediates Mesenchymal Stem Cell Senescence via Regulation of Mitochondrial Dynamics

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4915149 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Xin Li ◽

Yimei Hong ◽

Haiwei He ◽

Guojun Jiang ◽

Wei You ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Signaling Pathway ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Fibroblast Growth Factor 21 ◽

Early Passage ◽

Ampk Signaling ◽

Novel Strategy

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

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Comparison of Mesenchymal Stem Cell Markers in Multiple Human Adult Stem Cells

International Journal of Stem Cells ◽

10.15283/ijsc.2014.7.2.118 ◽

2014 ◽

Vol 7 (2) ◽

pp. 118-126 ◽

Cited By ~ 104

Author(s):

Masoud Maleki ◽

Farideh Ghanbarvand ◽

Mohammad Reza Behvarz ◽

Mehri Ejtemaei ◽

Elham Ghadirkhomi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Adult Stem Cells ◽

Stem Cell Markers ◽

Cell Markers ◽

Human Adult

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MODELING PANCREATIC PATHOPHYSIOLOGY USING GENOME EDITING OF ADULT STEM CELL- AND INDUCED PLURIPOTENT STEM CELL (iPSC)-DERIVED ORGANOIDS

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00329.2020 ◽

2021 ◽

Author(s):

Sabrina T. Hirshorn ◽

Nina Steele ◽

Yana Zavros

Keyword(s):

Stem Cell ◽

Genome Editing ◽

Pluripotent Stem Cell ◽

Adult Stem Cells ◽

Defense Mechanism ◽

Adult Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Organ Development ◽

Induced Pluripotent

In recent years, organoids have become a novel in vitro method to study gastrointestinal organ development, physiology and disease. An organoid, in short, may be defined as a miniaturized organ that can be grown from adult stem cells in vitro and studied at the microscopic level. Organoids have been used in multitudes of different ways to study the physiology of different human diseases including gastrointestinal cancers such as pancreatic cancer. The development of genome editing based on the bacterial defense mechanism CRISPR/Cas9 has emerged as laboratory tool that provides the opportunity to study the effects of specific genetic changes on organ development, physiology and disease. The CRISPR/Cas9 approach can be combined with organoid technology including the use of induced pluripotent stem cell (iPSC)-derived and tissue-derived organoids. The goal of this review is to provide highlights on the development of organoid technology, and the use of this culture system to study the pathophysiology of specific mutations in the development of pancreatic and gastric cancers.

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A Novel Strategy to Enhance Mesenchymal Stem Cell Migration Capacity and Promote Tissue Repair in an Injury Specific Fashion

Cell Transplantation ◽

10.3727/096368912x653246 ◽

2013 ◽

Vol 22 (3) ◽

pp. 423-436 ◽

Cited By ~ 74

Author(s):

C. Xinaris ◽

M. Morigi ◽

V. Benedetti ◽

B. Imberti ◽

A. S. Fabricio ◽

...

Keyword(s):

Stem Cell ◽

Cell Migration ◽

Mesenchymal Stem Cell ◽

Tissue Repair ◽

Stem Cell Migration ◽

Novel Strategy ◽

Migration Capacity

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Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A-type lamins as intrinsic modulators of ageing in adult stem cells and their niches

Journal of Anatomy ◽

10.1111/j.1469-7580.2008.00928.x ◽

2008 ◽

Vol 213 (1) ◽

pp. 5-25 ◽

Cited By ~ 46

Author(s):

Vanja Pekovic ◽

Christopher J. Hutchison

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Tissue Regeneration ◽

Adult Stem Cells ◽

Adult Stem Cell ◽

Stem Cell Maintenance ◽

Cell Maintenance

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Adult Stem Cell Therapeutics in Diabetic Retinopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20194876 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4876 ◽

Cited By ~ 2

Author(s):

Sriprachodaya Gaddam ◽

Ramesh Periasamy ◽

Rajashekhar Gangaraju

Keyword(s):

Stem Cells ◽

Diabetic Retinopathy ◽

Stem Cell ◽

Adult Stem Cells ◽

Adult Stem Cell ◽

Target Tissue ◽

Cell Therapeutics ◽

Potential Safety ◽

Working Age ◽

Stem Cell Therapeutics

Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell therapeutics, have shown variable efficacy in preclinical models due to the multi-faceted nature of the disease. Among the various adult stem cells, mesenchymal stem cells, especially those derived from adipose tissue and bone marrow, have been explored as a possible treatment for DR. This review summarizes the current literature around the various adult stem cell treatments for the disease and outlines the benefits and limitations of the therapeutics that are being explored in the field. The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue. Various methods of mesenchymal stem cell priming to adapt to a hostile retinal microenvironment have been discussed. Current clinical trials and potential safety concerns have been examined, and the future directions of stem cell therapeutics in DR have also been contemplated.

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