Bilayer Silk Fibroin/Sodium Alginate Scaffold Delivered hUC-MSCs to Enhance Skin Scarless Healing and Hair Follicle Regeneration with the IRE1/XBP1 Pathway Inhibition

Abstract

Efficient local delivery of mesenchymal stem cells (MSCs) is a decisive factor for their application in regeneration processes. Here, we prepared a biomimetic bilayer silk fibroin/sodium alginate (SF/SA) scaffold to deliver human umbilical mesenchymal stem cells (hUC-MSCs) for wound healing. An SA membrane was prepared by the casting method on the upper layer of the scaffold to simulate the dense epidermal structure. On the lower layer, porous materials simulating the loose structure of the dermis were formed by the freeze-drying method. In vitro, the scaffold was proven to have a high-density pore structure, good swelling property, and suitable degradation rate. The hUC-MSCs could survive on the scaffold for up to 14 days and maintain cell stemness for at least 7 days. In vivo, SF/SA scaffolds loaded with hUC-MSCs (M-SF/SA) were applied to full-thickness defect wounds and compared with the local injection of hUC-MSCs. The M-SF/SA group showed excellent therapeutic efficacy, characterized by induction of macrophage polarization, regulation of TGF-β expression and collagen components, and enhancement of vascular regeneration, thereby preventing scar formation and promoting hair follicle regeneration. Furthermore, the expression of endoplasmic reticulum stress markers IRE1, XBP1, and CHOP was inhibited significantly in M-SF/SA treatment. In conclusion, the bilayer SF/SA scaffold is an ideal delivery platform for hUC-MSCs, and the M-SF/SA system could locally promote scarless skin healing and hair follicle regeneration by alleviating the IRE1/XBP1 signal pathway.

Reactive Oxygen Species Scavenging Injectable Hydrogel Potentiates the Therapeutic Potential of Mesenchymal Stem Cells in Skin Flap Regeneration

“…Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that possess differentiation abilities, immunomodulatory effects, and homing properties. They are considered one of the most promising biological agents for enhancing tissue regenerative capacity. − Multiple experiments have indicated that MSCs play a vital role in neovascularization of ischemic tissues, including wound healing, , ischemia of the hind limb, and myocardial infarction . Cell-based therapies utilizing MSCs can also be employed as an effective method to regulate vascularization and immune responses through the secretion of growth factors, cytokines and exosomes, ultimately improving skin flap survival and functional recovery. , However, the failure of most clinical stage MSC therapies suggests that the inherent therapeutic benefits of MSCs when administered to humans are not as vigorous as demonstrated in preclinical studies .…”

“…Recently, the transplantation of cells with biomaterial scaffolds has emerged as a promising strategy for cell-based therapies , due to the scaffolds’ ability to prolong cell retention, providing appropriate cellular niches for the implanted cells and guide tissue regrowth. ,, The synergistic roles of MSCs and hydrogel scaffolds in skin flap regeneration have also been demonstrated. , However, the significant level reactive oxygen species (ROS) and inflammatory response in the injured tissue were ignored, which not only jeopardized cell proliferation and functions but also triggered apoptosis, , ultimately impeding tissue regeneration. − Therefore, it is critical to regulate the harsh microenvironment and promote cell viability to ensure the survival of MSCs following implantation and regeneration of damaged tissue.…”