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Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential.
J Bone Miner Res. 2017 Jun; 32(6):1368-1385.JB

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+Show Affiliations

Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario. London, ON, Canada.Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario. London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.Department of Neurology, Stanford University Medical Center, Palo Alto, CA, USA.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario. London, ON, Canada. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28177159

Citation

Esseltine, Jessica L., et al. "Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 32, no. 6, 2017, pp. 1368-1385.
Esseltine JL, Shao Q, Brooks C, et al. Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential. J Bone Miner Res. 2017;32(6):1368-1385.
Esseltine, J. L., Shao, Q., Brooks, C., Sampson, J., Betts, D. H., Séguin, C. A., & Laird, D. W. (2017). Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 32(6), 1368-1385. https://doi.org/10.1002/jbmr.3098
Esseltine JL, et al. Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential. J Bone Miner Res. 2017;32(6):1368-1385. PubMed PMID: 28177159.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential. AU - Esseltine,Jessica L, AU - Shao,Qing, AU - Brooks,Courtney, AU - Sampson,Jacinda, AU - Betts,Dean H, AU - Séguin,Cheryle A, AU - Laird,Dale W, Y1 - 2017/04/05/ PY - 2016/09/29/received PY - 2017/01/26/revised PY - 2017/02/01/accepted PY - 2017/2/9/pubmed PY - 2018/3/23/medline PY - 2017/2/9/entrez KW - CHONDROGENIC DIFFERENTIATION KW - CONNEXIN KW - GAP JUNCTIONAL INTERCELLULAR COMMUNICATION KW - GJIC KW - INDUCED PLURIPOTENT STEM CELL KW - IPSC KW - OSTEOGENIC DIFFERENTIATION SP - 1368 EP - 1385 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 32 IS - 6 N2 - 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. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/28177159/Connexin43_Mutant_Patient_Derived_Induced_Pluripotent_Stem_Cells_Exhibit_Altered_Differentiation_Potential_ L2 - https://doi.org/10.1002/jbmr.3098 DB - PRIME DP - Unbound Medicine ER -