Connexin43 is Dispensable for Early Stage Human Mesenchymal Stem Cell Adipogenic Differentiation But is Protective against Cell Senescence.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, 2011-

Adipogenesis* ; Cell Differentiation* ; Cellular Senescence*; Connexin 43/*metabolism ; Mesenchymal Stem Cells/*cytology; Connexin 43/deficiency ; Gene Expression Regulation ; Humans ; Time Factors

In the last couple of decades, there has been a growing optimism surrounding the potential transformative use of human mesenchymal stem cells (MSCs) and human-induced pluripotent stem cells (iPSCs) for regenerative medicine and disease treatment. In order for this to occur, it is first essential to understand the mechanisms underpinning their cell-fate specification, which includes cell signaling via gap junctional intercellular communication. Here, we investigated the role of the prototypical gap junction protein, connexin43 (Cx43), in governing the differentiation of iPSCs into MSCs and MSC differentiation along the adipogenic lineage. We found that control iPSCs, as well as iPSCs derived from oculodentodigital dysplasia patient fibroblasts harboring a GJA1 (Cx43) gene mutation, successfully and efficiently differentiated into LipidTox and perilipin-positive cells, indicating cell differentiation along the adipogenic lineage. Furthermore, the complete CRISPR-Cas9 ablation of Cx43 from iPSCs did not prevent their differentiation into bona fide MSCs or pre-adipocytes, strongly suggesting that even though Cx43 expression is upregulated during adipogenesis, it is expendable. Interestingly, late passage Cx43-ablated MSCs senesced more quickly than control cells, resulting in failure to properly differentiate in vitro. We conclude that despite being upregulated during adipogenesis, Cx43 plays no detectable role in the early stages of human iPSC-derived MSC adipogenic differentiation. However, Cx43 may play a more impactful role in protecting MSCs from premature senescence.

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148630 Canada CIHR

Keywords: CRISPR-Cas9; adipogenesis; connexin43; gap junctional intercellular communication; mesenchymal stem cells; oculodentodigital dysplasia; senescence

0 (Connexin 43)

Date Created: 20190914 Date Completed: 20200706 Latest Revision: 20231014

20240829

PMC6770901

10.3390/biom9090474

31514306