Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential.

Abstract

We present for the first time the generation of induced pluripotent stem cells (iPSCs) from a patient with a connexin-linked disease. The importance of gap junctional intercellular communication in bone homeostasis is exemplified by the autosomal dominant developmental disorder oculodentodigital dysplasia (ODDD), which is linked to mutations in the GJA1 (Cx43) gene. ODDD is characterized by craniofacial malformations, ophthalmic deficits, enamel hypoplasia, and syndactyly. In addition to harboring a Cx43 p.V216L mutation, ODDD iPSCs exhibit reduced Cx43 mRNA and protein abundance when compared to control iPSCs and display impaired channel function. Osteogenic differentiation involved an early, and dramatic downregulation of Cx43 followed by a slight upregulation during the final stages of differentiation. Interestingly, osteoblast differentiation was delayed in ODDD iPSCs. Moreover, Cx43 subcellular localization was altered during chondrogenic differentiation of ODDD iPSCs compared to controls and this may have contributed to the more compact cartilage pellet morphology found in differentiated ODDD iPSCs. These studies highlight the importance of Cx43 expression and function during osteoblast and chondrocyte differentiation, and establish a potential mechanism for how ODDD-associated Cx43 mutations may have altered cell lineages involved in bone and cartilage development. © 2017 American Society for Bone and Mineral Research.

• Authors: Jessica L Esseltine, Qing Shao, Courtney Brooks, Jacinda Sampson, Dean H Betts, Cheryle A Séguin, Dale W Laird
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 32 Issue 6 Pg. 1368-1385 (Jun 2017) ISSN: 1523-4681 [Electronic] United States
• PMID: 28177159 (Publication Type: Journal Article)
• Copyright: © 2017 American Society for Bone and Mineral Research.

Chemical References

• Connexin 43
• Collagen

Topics

• Cell Differentiation
• Chondrogenesis
• Collagen (metabolism)
• Connexin 43 (genetics)
• Craniofacial Abnormalities (genetics, pathology)
• Dermis (pathology)
• Eye Abnormalities (genetics, pathology)
• Fibroblasts (metabolism)
• Foot Deformities, Congenital (genetics, pathology)
• Gap Junctions (metabolism)
• Humans
• Induced Pluripotent Stem Cells (metabolism, pathology)
• Mutation (genetics)
• Osteogenesis
• Syndactyly (genetics, pathology)
• Tooth Abnormalities (genetics, pathology)