A comparison of BMP2 delivery by coacervate and gene therapy for promoting human muscle-derived stem cell-mediated articular cartilage repair

Abstract

BackgroundOsteoarthritis and cartilage injury treatment is an unmet clinical need. Therefore, development of new approaches to treat these diseases is critically needed. Previous work in our laboratory has shown that murine muscle-derived stem cells (MDSCs) can efficiently repair articular cartilage in an osteochondral and osteoarthritis model. However, the cartilage repair capacity of human muscle-derived stem cells has not been studied which prompt this study.MethodIn this study, we tested the in vitro chondrogenesis ability of six populations of human muscle-derived stem cells (hMDSCs), before and after lenti-BMP2/GFP transduction using pellet culture and evaluated chondrogenic differentiation of via histology and Raman spectroscopy. We further compared the in vivo articular cartilage repair of hMDSCs stimulated with BMP2 delivered through coacervate sustain release technology and lenti-viral gene therapy-mediated gene delivery in a monoiodoacetate (MIA)-induced osteoarthritis (OA) model. We used microCT and histology to evaluate the cartilage repair.ResultsWe observed that all hMDSCs were able to undergo chondrogenic differentiation in vitro. As expected, lenti-BMP2/GFP transduction further enhanced the chondrogenic differentiation capacities of hMDSCs, as confirmed by Alcian blue and Col2A1staining as well as Raman spectroscopy analysis. We observed through micro-CT scanning, Col2A1 staining, and histological analyses that delivery of BMP2 with coacervate could achieve a similar articular cartilage repair to that mediated by hMDSC-LBMP2/GFP. We also found that the addition of soluble fms-like tyrosine kinase-1 (sFLT-1) protein further improved the regenerative potential of hMDSCs/BMP2 delivered through the coacervate sustain release technology. Donor cells did not primarily contribute to the repaired articular cartilage since most of the repair cells are host derived as indicated by GFP staining.ConclusionsWe conclude that the delivery of hMDSCs and BMP2 with the coacervate technology can achieve a similar cartilage repair relative to lenti-BMP2/GFP-mediated gene therapy. The use of coacervate technology to deliver BMP2/sFLT1 with hMDSCs for cartilage repair holds promise for possible clinical translation into an effective treatment modality for osteoarthritis and traumatic cartilage injury.

RETRACTED ARTICLE: Exosome-delivered BMP-2 and polyaspartic acid promotes tendon bone healing in rotator cuff tear via Smad/RUNX2 signaling pathway

“…SIRT1 promoted BMP-2-induced chondrogenic differentiation of MSCs and reduced the apoptosis and decomposition of the extracellular matrix under oxidative stress [ 38 ]. It has also been demonstrated that BMP-2 delivery by coacervate and gene therapy can promote human muscle-derived stem cell-mediated articular cartilage repair [ 23 ]. In fact, studies have showed that cartilage differentiation plays crucial roles in tendon and bone interface healing [ 39 ].…”

Rejuvenated Stem/Progenitor Cells for Cartilage Repair Using the Pluripotent Stem Cell Technology

“…One of the strategies toward improving the outcome of exogenous or endogenous reparative cell-based cartilage repair is to optimize the local milieu for such cells to properly rebuild the articular cartilaginous tissue in the damaged site, using factors that are known to directly or indirectly enhance chondrogenesis from MSCs and SSCs in vitro and in vivo. Such factors include transforming growth factor beta (TGF-β) [ 25 , 26 , 27 ], bone morphogenetic protein (BMP) [ 28 , 29 , 30 , 31 ], fibroblast growth factor 18 (FGF18) [ 32 , 33 ], insulin-like growth factor 1 (IGF1) [ 34 , 35 ], and stromal cell-derived factor 1 (SDF1/CXCL12) [ 36 , 37 ]. These factors have been preclinically and clinically tested and resulted in some positive outcomes [ 8 ].…”

Simvastatin Enhances the Chondrogenesis But Not the Osteogenesis of Adipose-Derived Stem Cells in a Hyaluronan Microenvironment

“…Among the chondrogenic growth factors, bone morphogenetic protein (BMP)-4, BMP-6, BMP-7, transforming growth factor (TGF)-βs, insulin-like growth factor (IGF)-1 and BMP-2 have been demonstrated to be the most effective [ 12 , 13 , 14 ]. BMP-2 is a member of the TGF-β superfamily and a potent regulator of cartilage growth and development [ 5 , 15 , 16 ]. BMP-2 has also been applied as a chondroinductive factor to promote MSC chondrogenesis [ 12 , 15 , 16 , 17 , 18 ].…”

“…BMP-2 is a member of the TGF-β superfamily and a potent regulator of cartilage growth and development [ 5 , 15 , 16 ]. BMP-2 has also been applied as a chondroinductive factor to promote MSC chondrogenesis [ 12 , 15 , 16 , 17 , 18 ]. However, BMP-2 also exerts osteogenic effects on MSCs [ 19 , 20 , 21 , 22 ].…”