Mesenchymal Stromal Cells and Extracellular Vesicles

Delco, M.L.; Srivastava, Nikita

doi:10.1007/978-3-030-79485-9_13

Cited by 2 publications

(1 citation statement)

References 186 publications

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“…Mesenchymal stromal cells (MSCs) are being widely investigated as regenerative therapies, and increasing evidence suggests MSCs can relieve symptoms of OA including pain and joint dysfunction, as well as preserve cartilage (15, 16). While the mechanisms governing the beneficial effects of implanted cells remain unclear, contemporary evidence indicates that MSCs act mainly by modulating the joint environment via their secreted products, which inhibit catabolic signaling pathways and promote anabolic responses (17).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Fahey

Bennett

Thomas

et al. 2022

Preprint

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Avascular soft tissues of the skeletal system, including articular cartilage, have limited healing capacity, in part due to their low metabolic activity. No drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Therefore, mesenchymal stromal cell (MSC)-based regenerative therapies are increasingly common in the treatment of OA, but questions regarding their clinical efficacy and mechanisms of action remain unanswered. Our group recently reported that mitochondrial dysfunction is one of the earliest responses of cartilage to injury, resulting in chondrocyte death, extracellular matrix degeneration, and ultimately OA. MSCs have been found to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. Stressed chondrocytes increased expression of genes related to inflammation and senescence, further supporting the link between mitochondrial dysfunction and transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When MSCs were exposed to mechanically injured cartilage they localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.Significance StatementRecent evidence suggests that although articular cartilage is avascular and relatively metabolically quiescent, acute injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. We present the first evidence that MSCs donate mitochondria to articular chondrocytes undergoing mitochondrial dysfunction in vitro and in situ. These findings support a new role for MSCs in the context of cartilage injury and OA, and intercellular mitochondrial transfer may represent a new biological approach to augment mitochondrial capacity in injured chondrocytes. This work establishes multiple experimental models to study MSC mitochondrial donation for the treatment of OA and related degenerative diseases of avascular orthopedic tissues.

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Section: Introductionmentioning

confidence: 99%

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Fahey

Bennett

Thomas

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

Fahey

Bennett

Thomas

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Articular cartilage has limited healing capacity and no drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Mesenchymal stromal cell (MSC)-based regenerative therapies for OA are increasingly common, but questions regarding their mechanisms of action remain. Our group recently reported that although cartilage is avascular and relatively metabolically quiescent, injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. MSCs are known to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known to induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When exposed to mechanically injured cartilage, MSCs localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.

show abstract

Mesenchymal Stromal Cells and Extracellular Vesicles

Cited by 2 publications

References 186 publications

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

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