Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a.
The success of cell-based therapies to restore joint cartilage requires an optimal source of reparative progenitor cells and tight control of their differentiation into a permanent cartilage phenotype. Bone morphogenetic protein 2 (BMP-2) has been extensively shown to promote mesenchymal cell differentiation into chondrocytes in vitro and in vivo. Conversely, developmental studies have demonstrated decreased chondrocyte maturation by Wingless-Type MMTV Integration Site Family, Member 5A (Wnt5a). Thus, we hypothesized that treatment of human embryonic stem cell (hESC)-derived chondroprogenitors with BMP-2 followed by Wnt5a may control the maturational progression of these cells into a hyaline-like chondrocyte phenotype. We examined the effects of sustained exposure of hESC-derived mesenchymal-like progenitors to recombinant Wnt5a or BMP-2 in vitro. Our data indicate that BMP-2 promoted a strong chondrogenic response leading to terminal maturation, whereas recombinant Wnt5a induced a mild chondrogenic response without promoting hypertrophy. Moreover, Wnt5a suppressed BMP-2-mediated chondrocyte maturation, preventing the formation of fibrocartilaginous tissue in high-density cultures treated sequentially with BMP-2 and Wnt5a. Implantation of scaffoldless pellets of hESC-derived chondroprogenitors pretreated with BMP-2 followed by Wnt5a into rat chondral defects induced an articular-like phenotype in vivo. Together, the data establish a novel role for Wnt5a in controlling the progression from multipotency into an articular-like cartilage phenotype in vitro and in vivo. Stem Cells Translational Medicine 2017;6:40-50.
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Jason D
JD
Gibson
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Michael B
MB
O'Sullivan
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Farhang
F
Alaee
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
David N
DN
Paglia
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Ryu
R
Yoshida
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Rosa M
RM
Guzzo
Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, UConn Stem Cell Institute, UConn Health, University of Connecticut, Farmington, Connecticut, USA.
Hicham
H
Drissi
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D011923:Rats, Nude; D012038:Regeneration / Q000187:drug effects*; D000071818:Wnt-5a Protein / Q000494:pharmacology*
D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D000071818:Wnt-5a Protein
Articular cartilage; BMP-2; Embryonic stem cells; Mesenchymal stem cells; Wnt5a