Sulfated glycosaminoglycans in decellularized placenta matrix as critical regulators for cutaneous wound healing

Perinatal-related tissues, such as the placenta, umbilical cord, and amniotic membrane, are generally discarded after delivery and are increasingly attracting attention as alternative sources for decellularized extracellular matrix (dECM) isolation. Recent studies indicate that glycosaminoglycans (GAGs) in the dECM play key roles during tissue regeneration. However, the dECM is organ specific, and the glycosaminoglycanomics of dECMs from perinatal tissues and the regulatory function of GAGs have been poorly investigated. In this study, we explored the glycosaminoglycanomics of dECMs from the placenta, umbilical cord and amniotic membrane. We hypothesized that the therapeutic effects of dECMs are related to the detailed composition of GAGs. Hydrogels of dECM derived from perinatal tissues were generated, and glycosaminoglycanomics analysis was employed to identify the cues that promote tissue repair and regeneration in a murine cutaneous wound-healing model. We utilized highly sensitive liquid chromatography-tandem mass spectrometry for glycosaminoglycanomics analysis. Our results revealed that placenta-derived dECM (PL-dECM) hydrogel has higher contents of chondroitin sulfate (CS) and heparan sulfate (HS). In addition, molecular imaging showed that the PL-dECM hydrogel exerted the best anti-inflammatory and proangiogenic effects in the skin wound healing model. Further in vitro analyses demonstrated that CS with 6-O-sulfo group (CS-6S) has an anti-inflammatory effect, while HS with 6-O-sulfo group (HS-6S) plays a crucial role in angiogenesis. In conclusion, this study highlights the critical roles of GAGs in perinatal tissue-derived dECMs by promoting angiogenesis and inhibiting inflammation and indicates that it is feasible to utilize 6-sulfated GAG-enriched placental dECM hydrogel as an attractive candidate for tissue engineering and drug delivery.