Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a

Abstract

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

Human Platelet Lysate Improves Bone Forming Potential of Human Progenitor Cells Expanded in Microcarrier-Based Dynamic Culture

“…WNT5A has also been reported to be a repressor of PPARγ expression which is in sync with our observations of high WNT5A expression, lower PPARγ expression, and lower adipogenic potential of hPDCs expanded in HPL. Both BMP2 and WNT5A specifically have also been reported to promote MSC osteogenesis . The high expression level of these two markers in our HPL supplemented culture may partially explain the marked difference in in vivo bone formation as observed in the nude mice model.…”

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

“…Chondrogenic markers SOX9 and COL2A1 increased whereas the expression of hypertrophy markers; COL10A1 and ALP, decreased. In the same study, 66 the effect of BMP2 was found to upregulate early chondrogenic markers and proteoglycan production, attaining higher ratios than wnt5a. However, BMP2 also significantly increased expression of hypertrophic markers.…”

“…No work was identified that applied wnt5a directly onto ESC for chondrogenic differentiation. However, Gibson and colleagues 66 have applied wnt5a supplementation with pellet cultures of ESCs that were predifferentiated to take on a MSC phenotype. Similar effects were reported by wnt5a as observed with wnt3a 66 viz.…”

“…The sequential treatment of BMP2 and wnt5a showed beneficial for inducing articular chondrocyte-like phenotypes, constituting initial chondrogenic induction via BMP2, followed by wnt5a supplementation on the fifth day to maintain the chondrogenic phenotype and preventing hypertrophy. 66…”

Repair potential of nonsurgically delivered induced pluripotent stem cell-derived chondrocytes in a rat osteochondral defect model

“…Various researchers demonstrated that hiPSCs can differentiate into chondrocytes (Guzzo, Gibson, Xu, Lee, & Drissi, 2013;Koyama et al, 2013;Nam et al, 2017;Saito et al, 2013;Wei et al, 2012;Yamashita et al, 2013;Zhu et al, 2016). In vitro chondrogenesis from progenitor cells is usually induced in three-dimensional (3D) culture systems with or without scaffolds (i.e., pellet culture or micromass culture; Gibson et al, 2016, Lach, Trzeciak, Richter, Pawlicz, & Suchorska, 2014, Tsumaki, Okada, & Yamashita, 2015Nakagawa et al, 2016, Toh et al, 2009. However, to our knowledge, the effect of intra-articular injectable hiPSC-derived chondrocytes on cartilage recovery has not been demonstrated.…”