Toward zonally tailored scaffolds for osteochondral differentiation of synovial mesenchymal stem cells

Abstract

Synovium-derived mesenchymal stem cells (SMSCs) are an emerging cell source for regenerative medicine applications, including osteochondral defect (OCD) repair. However, in contrast to bone marrow MSCs, scaffold compositions which promote SMSC chondrogenesis/osteogenesis are still being identified. In the present manuscript, we examine poly(ethylene) glycol (PEG)-based scaffolds containing zonally-specific biochemical cues to guide SMSC osteochondral differentiation. Specifically, SMSCs were encapsulated in PEG-based scaffolds incorporating glycosaminoglycans (hyaluronan or chondroitin-6-sulfate [CSC]), low-dose of chondrogenic and osteogenic growth factors (TGFβ1 and BMP2, respectively), or osteoinductive poly(dimethylsiloxane) (PDMS). Initial studies suggested that PEG-CSC-TGFβ1 scaffolds promoted enhanced SMSC chondrogenic differentiation, as assessed by significant increases in Sox9 and aggrecan. Conversely, PEG-PDMS-BMP2 scaffolds stimulated increased levels of osteoblastic markers with significant mineral deposition. A “Transition” zone formulation was then developed containing a graded mixture of the chondrogenic and osteogenic signals present in the PEG-CSC-TGFβ1 and PEG-PDMS-BMP2 constructs. SMSCs within the “Transition” formulation displayed a phenotypic profile similar to hypertrophic chondrocytes, with the highest expression of collagen X, intermediate levels of osteopontin, and mineralization levels equivalent to “bone” formulations. Overall, these results suggest that a graded transition from PEG-CSC-TGFβ1 to PEG-PDMS-BMP2 scaffolds elicits a gradual SMSC phenotypic shift from chondrocyte to hypertrophic chondrocyte to osteoblast-like. As such, further development of these scaffold formulations for use in SMSC-based OCD repair is warranted.

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

“…To study the osteogenic capacity of SMSCs is of great value for translational medicine. As a promising seed cell, SMSCs are progressively used to promote bone healing and formation [24]. Thus, to further study the osteogenesis mechanism of SMSCs, it might be helpful to improve the osteogenic efficiency for bone regeneration.…”

Osteochondral Tissue Engineering: The Potential of Electrospinning and Additive Manufacturing

“…Accordingly, recent studies have also been adopting combined therapy strategies, in which multiple growth factors are delivered from a single tissue-engineered scaffold [ 153 , 154 ]. Such combinatory approaches may be of particular interest for OCTE, enabling the simultaneous delivery of factors involved in both SB and AC repair [ 155 , 156 , 157 ], even though obtaining positive results with dual growth factor delivery may not be straightforward [ 158 , 159 ]. An issue behind these combined therapy approaches is the difficulty in controlling growth factor release, so as to provide therapeutic dosages in an appropriate time frame for the promotion of cell homing, differentiation, and SB/AC tissue remodelling.…”

Perspectives on Synthetic Materials to Guide Tissue Regeneration for Osteochondral Defect Repair

“…For triphasic scaffolds, the middle phase is treated as a discrete layer with intermediate properties between bone and cartilage. , Often, “middle-ground” levels (between bone and cartilage) of scaffold porosity, − modulus, ,,, and material composition , are used to create a transition. Successful in vitro indications often show chondrocytic proliferation in a mineralized environment and expression phenotypical of hypertrophic chondrocytes, similar to that of the calcified cartilage layer. , Examples of these strategies include diverse composites (e.g., agarose with HAp, organic sol gel-coated calcium polyphosphate), , scaffold component orientations (e.g., arrayed platelike HAp), additives for osteochondral differentiation (e.g., Mg-doped wollastonite, icariin, or zinc oxide), − or components that promote a proregenerative environment (e.g., strontium or copper). , …”