Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101527581 Publication Model: Electronic Cited Medium: Internet ISSN: 1757-6512 (Electronic) Linking ISSN: 17576512 NLM ISO Abbreviation: Stem Cell Res Ther Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : BioMed Central
    • Subject Terms:
    • Abstract:
      Background: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes.
      Methods: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer.
      Results: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes.
      Conclusions: Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.
      (© 2024. The Author(s).)
    • Comments:
      Update of: bioRxiv. 2024 Mar 20:2024.03.18.585552. doi: 10.1101/2024.03.18.585552. (PMID: 38562828)
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    • Grant Information:
      Harry M. Zweig Memorial Fund for Equine Research Harry M. Zweig Memorial Fund for Equine Research; Cornell University Cornell University; K08AR068470 United States AR NIAMS NIH HHS; Orthopaedic Research Society Orthopaedic Research Society; R03 AR075929 United States AR NIAMS NIH HHS; R03AR075929 United States AR NIAMS NIH HHS
    • Contributed Indexing:
      Keywords: Arthritis; Cx43; GJA1; GJA1-20k; Gap junctions; MSCs; Osteoarthritis; Regenerative medicine
    • Accession Number:
      0 (Connexin 43)
      0 (Reactive Oxygen Species)
      0 (GJA1 protein, human)
    • Publication Date:
      Date Created: 20241010 Date Completed: 20241011 Latest Revision: 20241018
    • Publication Date:
      20241019
    • Accession Number:
      PMC11468299
    • Accession Number:
      10.1186/s13287-024-03932-9
    • Accession Number:
      39390589