Systemic impact molds mesenchymal stromal/stem cell aging

Reitinger, Stephan; Schimke, Magdalena; Klepsch, Sebastian; Sneeuw, Snezana de; Yani, Stella Lukas; Gaßner, Robert; Ertl, Peter; Lepperdinger, Günter

doi:10.1016/j.transci.2015.04.008

Cited by 14 publications

(11 citation statements)

References 44 publications

(37 reference statements)

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“…Unfortunately, in vitro culture has been shown to alter the capacity of MSCs to differentiate into various types of tissue [6]. For example, the “adipogenic switch,” or the loss of osteogenic potential and gain of adipogenic potential, has been observed in MSCs at advanced ages [7, 8]. More importantly, hBM-MSCs in late passages have been shown to become senescent [9].…”

Section: Introductionmentioning

confidence: 99%

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Shen

et al. 2019

Stem Cells International

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The application of human bone marrow mesenchymal stem cells (hBM-MSCs) in cell-based clinical therapies is hindered by the limited number of cells remaining after the initial isolation process and by cellular senescence following in vitro expansion. Understanding the process of in vitro senescence in hBM-MSCs would enable the development of strategies to maintain their vitality after cell culture. Herein, we compared the gene expression profiles of human embryonic stem cells and human BM-MSCs from donors of different ages. We first found that the expression of discoidin domain receptor 2 (DDR2) in adult donor-derived hBM-MSCs was lower than it was in the young donor-derived hBM-MSCs. Moreover, in vitro cultured late-passage hBM-MSCs showed significant downregulation of DDR2 compared to their early-passage counterparts, and siRNA inhibition of DDR2 expression recapitulated features of senescence in early-passage hBM-MSCs. Further, we found through knockdown and overexpression approaches that coactivator-associated arginine methyltransferase 1 (CARM1) regulated the expression level of DDR2 and the senescence of hBM-MSCs. Finally, chromatin immunoprecipitation analysis confirmed direct binding of CARM1 to the DDR2 promoter region with a high level of H3R17 methylation in early-passage hBM-MSCs, and inhibition of CARM1-mediated histone arginine methylation decreased DDR2 expression and led to cellular senescence. Taken together, our findings suggest that DDR2 plays a major role in regulating the in vitro senescence of hBM-MSCs and that CARM1-mediated histone H3 methylation might be the upstream regulatory mechanism controlling this function of DDR2.

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Section: Introductionmentioning

confidence: 99%

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Shen

et al. 2019

Stem Cells International

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“…There is considerable evidence that MSC senescence is considered as a contributing factor to aging and aging-related diseases 9 , 10 and replicative senescence impairs the regenerative potential of MSCs 11 . To better understand and monitor cell senescence in MSCs, it is necessary to have a reliable biomarker for identification of these cells.…”

Section: Introductionmentioning

confidence: 99%

Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells

et al. 2017

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Senescence in human mesenchymal stem cells (MSCs) not only contributes to organism aging and the development of a variety of diseases but also severely impairs their therapeutic properties as a promising cell therapy. Studies searching for efficient biomarkers that represent cellular senescence have attracted much attention; however, no single marker currently provides an accurate cell-free representation of cellular senescence. Here, we studied characteristics of MSC-derived microvesicles (MSC-MVs) that may reflect the senescence in their parental MSCs. We found that senescent late passage (LP) MSCs secreted higher levels of MSC-MVs with smaller size than did early passage (EP) MSCs, and the level of CD105+ MSC-MVs decreased with senescence in the parental MSCs. Also, a substantially weaker ability to promote osteogenesis in MSCs was observed in LP than EP MSC-MVs. Comparative analysis of RNA sequencing showed the same trend of decreasing number of highly-expressed miRNAs with increasing number of passages in both MSCs and MSC-MVs. Most of the highly-expressed genes in LP MSCs and the corresponding MSC-MVs were involved in the regulation of senescence-related diseases, such as Alzheimer's disease. Furthermore, based on the miRNA profiling, transcription factors (TF) and genes regulatory networks of MSC senescence, and the datasets from GEO database, we confirmed that expression of miR-146a-5p in MSC-MVs resembled the senescent state of their parental MSCs. Our findings provide evidence that MSC-MVs are a key factor in the senescence-associated secretory phenotype of MSCs and demonstrate that their integrated characteristics can dynamically reflect the senescence state of MSCs representing a potential biomarker for monitoring MSC senescence.

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“…It is generally believed that cells behave very differently when grown in 3D, as cell-cell contacts or production and deposition of matrix will greatly differ compared to 2D cell culture in plastic dishes [34]. Straightforward unsophisticated biomaterial-assisted growth could be the first step towards experimental analysis of organotypic cell biology [35, 36]. Noteworthy in this context is the fact that treatment with serum-containing culture media caused no apparent reduction of long-term stability.…”

Section: Discussionmentioning

confidence: 99%

Hard Tissue Augmentation of Aged Bone by Means of a Tin-Free PLLA-PCL Co-Polymer Exhibiting in vivo Anergy and Long-Term Structural Stability

et al. 2019

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Background: Due to aging, tissue regeneration gradually declines. Contemporary strategies to promote tissue-specific regeneration, in particular in elderly patients, often include synthetic material apt for implantation primarily aiming at upholding body functions and regaining appropriate anatomical and functional integrity. Objective: Biomaterials suitable for complex reconstruction surgical procedures have to exert high physicochemical stability and biocompatibility. Method: A polymer made of poly-L-lactic acid and poly-ε-caprolactone was synthesized by means of a novel tin-free catalytic process. The material was tested in a bioreactor-assisted perfusion culture and implanted in a sheep model for lateral augmentation of the mandible. Histological and volumetric evaluation was performed 3 and 6 months post-implantation. Results: After synthesis the material could be further refined by cryogrinding and sintering, thus yielding differently porous scaffolds that exhibited a firm and stable appearance. In perfusion culture, no disintegration was observed for extended periods of up to 7 weeks, while mesenchymal stromal cells readily attached to the material, steadily proliferated, and deposited extracellular calcium. The material was tested in vivo together with autologous bone marrow-derived stromal cells. Up to 6 months post-implantation, the material hardly changed in shape with composition also refraining from foreign body reactions. Conclusion: Given the long-term shape stability in vivo, featuring imperceptible degradation and little scarring as well as exerting good compatibility to cells and surrounding tissues, this novel biomaterial is suitable as a space filler in large anatomical defects.

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Systemic impact molds mesenchymal stromal/stem cell aging

Cited by 14 publications

References 44 publications

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells

Hard Tissue Augmentation of Aged Bone by Means of a Tin-Free PLLA-PCL Co-Polymer Exhibiting in vivo Anergy and Long-Term Structural Stability

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