Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine

Charif, Naceur; Li, Y.Y.; Targa, Laurie; Zhang, L.; Ye, J.S.; Li, Y.P.; Stoltz, Jean‐François; Han, Hui; Isla, Natalia de

doi:10.3233/bme-171624

Cited by 33 publications

(30 citation statements)

References 36 publications

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“…In addition, clinical application of MSC requires an ex vivo expansion step, in which cells undergo an inevitable replicative aging process (6). Mounting evidence suggests aging affects MSC function, including proliferation, clonogenicity, differentiation potential, immunomodulation properties, telomere length, migration, and adhesion (7). Aging also impairs MSC secretome related to its angiogenic potential, reducing its clinical efficacy (8).…”

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confidence: 99%

Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

et al. 2018

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The age‐related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb‐B2 receptor tyrosine kinase 4 (ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged‐MSC), ERBB4‐engineered aged MSC (ER4‐aged‐MSC) conferred resistance to oxidative stress‐induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4‐aged‐MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged‐MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v‐akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4‐aged‐MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.—Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways. FASEB J. 33, 4559–4570 (2019). http://www.fasebj.org

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confidence: 99%

Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

et al. 2018

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“…We also have successfully isolated these cells from older donors (up to 56 years) and demonstrated expansion in culture (unpublished data). However, we intentionally focused on young donors in this report given the literature suggesting higher frequencies and proliferation rates of MSC derived from various tissues obtained from young donors compared to their older counterparts [49][50][51][52][53][54][55]. Therefore, in the absence of impacts from environment and disease status, the lowest COG to manufacture vBA-MSC would be from young donors.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Large Source of Primary Mesenchymal Stem Cells Tightly Adhered to Bone Surfaces of Human Vertebral Body Marrow Cavities

Johnstone

Miller

Beck

et al. 2020

Preprint

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Therapeutic allogeneic mesenchymal stem/stromal cells (MSC) are currently in clinical trials for evaluating their effectiveness in treating many different disease indications. Eventual commercialization for broad distribution will require further improvements in manufacturing processes to economically manufacture MSC at sufficient scales required to satisfy projected demands. A key contributor to the present high cost of goods (COG) for MSC manufacturing is the need to create master cell banks (MCBs) from multiple donors, which leads to variability in large-scale manufacturing runs. Therefore, the availability of large single donor depots of primary MSC would greatly benefit the cell therapy market by reducing costs associated with manufacturing.We have discovered that an abundant population of cells possessing all the hallmarks of MSC is tightly associated with the vertebral body (VB) bone matrix and are only liberated by proteolytic digestion. Here we demonstrate that these vertebral bone-adherent (vBA) MSC possess all the International Society of Cell and Gene Therapy (ISCT)-defined characteristics (e.g., plastic adherence, surface marker expression, and trilineage differentiation) of MSC and, therefore, have termed them vBA-MSC, to distinguish this population from loosely associated MSC recovered through aspiration or rinsing of the bone marrow (BM) compartment.Pilot banking and expansion was performed with vBA-MSC obtained from 3 deceased donors and it was demonstrated that bank sizes averaging 2.9x10 8 +1.35x10 8 vBA-MSC at passage one were obtainable from only 5 g of digested VB bone fragments. Each bank of cells demonstrated robust proliferation through a total of 9 passages without significant reduction in population doubling times. The theoretical total cell yield from the entire amount of bone fragments (approximately 300g) from each donor with limited expansion through 4 passages is 100 trillion (1x10 14 ) vBA-MSC, equating to over 10 5 doses at 10x10 6 cells/kg for an average 70 kg recipient. Thus, we have established a novel and plentiful source of MSC which will benefit the cell therapy market by overcoming manufacturing and regulatory inefficiencies due to donorto-donor variability.

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“…Although data on the functionality of MSCs isolated from aged subjects with respect to young individuals are still debated in the literature, some consensual evidence appears. With the increase of donor age, MSCs from bone marrow are reported to show a decrease in proliferative and clonogenic/self-renewal capacities, characterized by the number of colony-forming unitfibroblasts (CFU-F) but no phenotypic change is correlated with age (for review, see Charif et al, 2017). Nevertheless, a low expression level of CD146 is associated with late passages and shortening of telomeres in MSCs (for review, see Fafian-Labora et al, 2019).…”

Section: Effect Of Aging On Mscsmentioning

confidence: 99%

Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging

Boulestreau

Maumus

Rozier

et al. 2020

Front. Cell Dev. Biol.

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Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell nonautonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells (MSCs) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent MSCs, the potential effect of MSC-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.

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Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine

Cited by 33 publications

References 36 publications

Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

Identification and Characterization of a Large Source of Primary Mesenchymal Stem Cells Tightly Adhered to Bone Surfaces of Human Vertebral Body Marrow Cavities

Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging

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