Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential.
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.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario. London, ON, Canada.
Jessica L
JL
Esseltine
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario. London, ON, Canada.
Qing
Q
Shao
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Courtney
C
Brooks
Department of Neurology, Stanford University Medical Center, Palo Alto, CA, USA.
Jacinda
J
Sampson
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Dean H
DH
Betts
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Cheryle A
CA
Séguin
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.
Dale W
http://orcid.org/0000-0002-4568-3285
DW
Laird
D002454:Cell Differentiation; D020219:Chondrogenesis; D003094:Collagen / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D020405:Dermis / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000473:pathology; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D010012:Osteogenesis; D013576:Syndactyly / Q000235:genetics / Q000473:pathology; D014071:Tooth Abnormalities / Q000235:genetics / Q000473:pathology
D018031:Connexin 43; D003094:Collagen
CHONDROGENIC DIFFERENTIATION; CONNEXIN; GAP JUNCTIONAL INTERCELLULAR COMMUNICATION; GJIC; INDUCED PLURIPOTENT STEM CELL; IPSC; OSTEOGENIC DIFFERENTIATION