Distinct role of perlecan plays in mesenchymal tissue regeneration through genetic and epigenetic modification

Perlecan is a critical component of basement membrane proteins in tissue development. However, there are few studies investigating direct impact of perlecan on mesenchymal tissue differentiation using genetic modification (gain- and loss-of-function mutations) and epigenetic modification (matrix microenvironment). In this report, Cas9-mediated knockout (KO) of heparin sulfate proteoglycan 2 (HSPG2) and overexpression (OE) in human fetal nucleus pulposus stem/progenitor cells (NPSCs) and adult infrapatellar fat pad-derived stem cells (IPFSCs) were evaluated for the influence on mesenchymal differentiation. Furthermore, decellularized ECM (dECM) deposited by fetal NPSCs with either HSPG2 KO or OE was evaluated for its rejuvenation effect on adult NPSCs in proliferation and mesenchymal differentiation. We found that adult IPFSCs confirmed the unique role of perlecan in mesenchymal differentiation of fetal NPSCs; dECM with perlecan overexpression significantly promoted adult NPSCs in chondrogenic capacity rather than osteogenic and adipogenic capacities, indicating a potential application of perlecan in engineering smart biomaterial for cartilage regeneration.