The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells

Li, Qianqian; Gao, Zewen; Chen, Ye; Guan, Min‐Xin

doi:10.1007/s13238-017-0385-7

Cited by 227 publications

(207 citation statements)

References 50 publications

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“…Recent studies have demonstrated the crucial roles of mitochondrial function in cellular energy metabolism and the multidifferentiation processes of MSCs (37,61). Differentiation is an energy-demanding process that relies on the overall quality and relative abundance of the mitochondrial population, including de novo synthesis of organelle components, formation of mitochondrial membranes, and division of preexisting mitochondria (62).…”

Section: Discussionmentioning

confidence: 99%

Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics

Lin

Pan

et al. 2019

FASEB j.

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Fracture remains one of the most common traumatic conditions in orthopedic surgery. The use of mesenchymal stem cells (MSCs) to augment fracture repair is promising. Leucine‐rich repeat‐containing GPCR 5 (Lgr5), a transmembrane protein, has been identified as a novel adult stem cell marker in various organs and tissues. However, the roles of Lgr5 in MSCs are not fully understood. In this study, we investigated cellular functions of Lgr5 in MSCs and its potential implications in treating fracture. Lgr5‐overexpressing MSCs (MSCLgr5) were established in murine SV40 promoter–driven luciferase reporter MSC line through virus transfection. Results of real‐time quantitative PCR and Western blot analysis confirmed the increased expression of Lgr5 in MSCLgr5. MSCLgr5 exhibited increased osteogenic capacity, which may result from elevated expression of β‐catenin and phosphorylated ERK1/2 within the nuclear region of cells. In contrast, inhibition of Lgr5 expression decreased the osteogenic differentiation ability of MSCs, accompanied with increased mitochondrial fragmentation and reduced expression of β‐catenin. Local transplantation of MSCLgr5 at fracture sites accelerated fracture healing via enhanced osteogenesis and angiogenesis. MSCLgr5 stimulated the tube formation capacity of HUVECs in a Matrigel coculture system in vitro significantly. Taken together, results suggest that Lgr5 is implicated in the cellular processes of osteogenic differentiation of MSCs through regulation of Wnt and ERK signaling pathways and mitochondrial dynamics in fusion and fission. Inhibition of Lgr5 expression induced increased mitochondrial fragmentation and suppression of osteogenesis. MSCLgr5 exhibited enhanced therapeutic efficacy for fracture healing, which may serve as a superior cell source for bone tissue repair.—Lin, W., Xu, L., Pan, Q., Lin, S., Feng, L., Wang, B., Chen, S., Li, Y., Wang, H., Li, Y., Wang, Y., Lee, W. Y. W., Sun, D., Li, G. Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics. FASEB J. 33, 8565–8577 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics

Lin

Pan

et al. 2019

FASEB j.

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“…The role of bioenergetics in influencing stem cell function is currently a hot topic in the stem cell field (30–33), but the impact of cellular bioenergetics on MSC function in particular is currently underappreciated (34). Moreover, the metabolic response of MSCs to irradiation, especially when considering the initial metabolic remodeling, is as of yet unknown.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

et al. 2019

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Mitochondria are highly dynamic organelles that respond rapidly to a number of stressors to regulate energy transduction, cell death signaling, and reactive oxygen species generation. We hypothesized that mitochondrial remodeling, comprising both structural and functional alterations, following ionizing radiation (IR) may underlie some of the tenets of radiobiology. Mesenchymal stem cells (MSCs) are precursors of bone marrow stroma and are altered in acute myeloid leukemia and by radiation and chemotherapy. Here, we report on changes in mitochondrial remodeling in human MSCs following X‐ray IR. Mitochondrial function was significantly increased in MSCs 4 h after IR as measured by mitochondrial oxygen consumption. Consistent with this elevated functional effect, electron transport chain supercomplexes were also increased in irradiated samples. In addition, mitochondria were significantly, albeit modestly, elongated, as measured by high‐throughput automated confocal imaging coupled with automated mitochondrial morphometric analyses. We also demonstrate in fibroblasts that mitochondrial remodeling is required for the adaptation of cells to IR. To determine novel mechanisms involved in mitochondrial remodeling, we performed quantitative proteomics on isolated mitochondria from cells following IR. Label‐free quantitative mitochondrial proteomics revealed notable changes in proteins in irradiated samples and identified prosaposin, and potentially its daughter protein saposin‐B, as a potential candidate for regulating mitochondrial function following IR. Whereas research into the biologic effects of cellular irradiation has long focused on nuclear DNA effects, our experimental work, along with that of others, is finding that mitochondrial effects may have broader implications in the field of stress adaptation and cell death in cancer (including leukemia) and other disease states.—Patten, D. A., Ouellet, M., Allan, D. S., Germain, M., Baird, S. D., Harper, M.‐E., Richardson, R. B. Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation. FASEB J. 33, 9263–9278 (2019). http://www.fasebj.org

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“…For example, high levels of ROS cause reduced proliferation, unexpected differentiation, aging, senescence, and apoptosis (Denu & Hematti, ). Physiological levels of ROS are strictly controlled in MSCs by changing the number of mitochondria, which generate ROS (Li, Gao, Chen, & Guan, ). In the undifferentiated state, MSCs have low numbers of mitochondria, while this number increases at the differentiated stage.…”

Section: Discussionmentioning

confidence: 99%

An anti‐oxidative cell culture dish inhibits intracellular reactive oxygen species accumulation and modulates pluripotency‐associated gene expression in mesenchymal stem cells

Ikeda

Inuzuka

Goto

et al. 2020

J Biomedical Materials Res

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Maintenance of the pluripotent state of mesenchymal stem cells (MSCs) during in vitro expansion is an important factor for the successful proliferation of MSCs possessing high differentiation capacity. However, the differentiation potential of MSCs can easily be lost during in vitro expansion, particularly at late passages. Reactive oxygen species (ROS) are signaling molecules that help to maintain MSC function; however, excessive ROS generation can induce senescence and impair both the differentiation capacity and proliferation of MSCs. In this study, we have designed an amphiphilic block copolymer (redox copolymer), which possesses ROS scavenging capacity in the hydrophobic site. When this redox copolymer was coated on cell culture dishes coupled with human E‐cadherin chimeric antibody (hE‐cad‐Fc), it had an antioxidative effect on cultured MSCs. We also confirmed that the redox polymer construct poly(ethylene glycol) tethered chain on the surface prevented nonspecific cell binding, whereas the co‐immobilized surface allowed high adhesion of E‐cadherin‐positive MSCs. Interestingly, the intracellular ROS level was significantly decreased by the prepared cell culture dish, despite ROS being scavenged only on the surface of the dish, on the cell exterior. Consequently, the cultured MSCs retained high expression levels of pluripotency‐associated genes, including SOX2.

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The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells

Cited by 227 publications

References 50 publications

Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics

Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

An anti‐oxidative cell culture dish inhibits intracellular reactive oxygen species accumulation and modulates pluripotency‐associated gene expression in mesenchymal stem cells

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