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Introduction: Mesenchymal stromal cells (MSCs) have the potential to respond to injury and aid in repair and regeneration of damaged tissues. Bone marrow and adipose tissue are the major sources of MSCs for clinical applications. Previous studies in animal models suggested that the regenerative activity of aged stem cells/MSCs can be enhanced by exposure to biomimetic microenvironments. The aim of our project was to investigate whether extracellular matrix (ECM) engineered from human induced pluripotent stem cells (hiPSCs) can enhance the regeneration potential of human bone marrow mesenchymal stromal cells (hBMSCs).
Methods: ECM was engineered from hiPSC-derived mesenchymal-like progenitors (hiPSC-MPs). ECM structure and composition were characterized before and after decellularization using immunofluorescence and biochemical assays. hBMSCs were cultured on the engineered ECM, and differentiated into osteogenic, chondrogenic and adipogenic lineages. Growth and differentiation responses were compared to tissue culture plastic controls.
Results and Discussion: Decellularized ECMs contained collagens type I and IV, fibronectin, laminin and < 5% residual DNA, suggesting efficient cell elimination. Cultivation hBMSCs on the ECM in osteogenic medium significantly increased hBMSC growth and markers of osteogenesis, including collagen deposition, alkaline phosphatase activity, osteogenic gene expression levels and matrix mineralization compared to plastic controls. hBMSCs cultivated in chondrogenic micromass culture significantly increased growth and markers of chondrogenesis, including glycosaminoglycans and collagen type II deposition, and chondrogenic gene expression. In contrast, adipogenic differentiation of hBMSCs on ECM resulted in significantly increased hBMSC growth on the ECM, but significantly reduced markers of adipogenic differentiation. Together, our studies suggest that BMSCs regenerative activity for osteogenesis and chondrogenesis could be enhanced, whereas adipogenic activity was diminished by the culture on hiPSC-engineered ECM. This counteracted the natural shift in hBMSC differentiation from osteogenesis to adipogenesis during aging. The contribution of specific matrix components and underlying mechanisms need to be further elucidated.
Conclusion: Our studies suggest that osteo- and chondrogenic regenerative activity can be enhanced by hBMSC culture on hiPSC-engineered ECM. Importantly, hiPSCs represent a scalable, clinically-relevant source for tissue engineering strategies employing engineered ECM materials.
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