Wound Healing by Allogeneic Transplantation of Specific Subpopulation From Human Umbilical Cord Mesenchymal Stem Cells

Abstract

In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient; nevertheless, when it fails, one of the main consequences is a chronic ulcerative skin defect, one of the most frequently recognized complications of diabetes. Most of these chronic venous ulcers do not heal with conventional treatment, leading to the appearance of infections and complications in the patient. Treatments based on the use of autologous mesenchymal stem cells (MSC) have been successful; however, its implementation entails complications. The umbilical cord offers an unlimited source of adult MSC (ucMSC) from the Wharton’s jelly tissue with the same relevant features for clinical applicability and avoiding difficulties. It has recently been characterized by one specific subpopulation derived from ucMSC, the differentiated mesenchymal cells (DMCs). This subpopulation expresses the human leukocyte antigen-G (HLA-G) molecule, a strong immunosuppressive checkpoint, and vascular endothelial growth factor (VEGF), the most potent angiogenic factor. Considering the importance of developing a more effective therapy for wound treatment, especially ulcerative skin lesions, we analyzed DMC safety, efficacy, and therapeutic potential. By immunohistochemistry, umbilical cords HLA-G and VEGF positive were selected. Flow cytometry revealed that 90% of the DMC subpopulation are HLA-G+, CD44+, CD73+, CD29+, CD105+, CD90+, and HLA-DR−. Reverse transcription-polymerase chain reaction revealed the expression of HLA-G in all of DMC subpopulations. Upon co-culture with the DMC, peripheral blood mononuclear cell proliferation was inhibited by 50%. In a xenograft transplantation assay, DMC improved wound healing with no signs of rejection of the transplanted cells in immunocompetent mice. This study confirms that HLA-G allows allogeneic cell transplantation, and VEGF is fundamental for the restoration of the failure in blood supply. DMC population has positive effects on wound healing by promoting local angiogenesis in skin lesions. DMC could play a very important role in regenerative medicine and could be a novel allogeneic cell-therapeutic tool for wound healing.

Single‐Cell and Spatial Transcriptomics Decodes Wharton's Jelly‐Derived Mesenchymal Stem Cells Heterogeneity and a Subpopulation with Wound Repair Signatures

“…[ 24 ] Second, CD29 was identified as another one of the candidate gene, as it is essential for wound healing, re‐epithelialization and vascularization [ 25 ] and has been shown to be a highly expressed gene of the MSC subpopulation beneficial to wound repair. [ 26 ] CD142 + WJ‐MSCs also have potential for wound repair. [ 11a ] Finally, based on comprehensive analysis of single‐cell data, gene function data and subcellular localization data, as well as a literature review, we identified CD142, CD29 and S100A9 as the candidate marker genes of this subpopulation for subsequent experiments.…”

Anti-Viral Activities of Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Against Human Respiratory Viruses

“…UCMSCs have received recent attention due to their powerful regenerative and immunomodulatory potential, and their EVs provide an emerging role in modulating the symptoms of various diseases ( Hollweck et al., 2012 ; Monguio-Tortajada et al., 2017 ; Lv et al., 2020 ; Liu et al., 2021 ; Palma et al., 2021 ). A recent study reported that co-culturing UCMSCs with IFV A/H5N1-infected alveolar epithelial cells significantly restored alveolar fluid clearance and protein permeability through the secretion of angiopoietin-1 and hepatocyte growth factor, factors which promote angiogenesis and cell growth and survival, respectively ( Loy et al., 2019 ).…”

“…In particular, UCMSCs are known for their immunosuppressive properties including low expression of major histocompatibility complex class I molecule and costimulatory factors such as CD80 and CD86 ( Tipnis et al., 2010 ). Recent studies indicate that exosomes derived from UCMSCs (U-exo) have a significant role in immune modulation, tissue regeneration and antimicrobial defense by directly modulating immune response and enhancing the proliferative potential of tissues ( Hollweck et al., 2012 ; Monguio-Tortajada et al., 2017 ; Lv et al., 2020 ; Liu et al., 2021 ; Palma et al., 2021 ). However, the role of U-exo on respiratory viral infection and pathogenesis has not been fully investigated.…”

Allogeneic transplantation of epidermal cell sheets followed by endoscopic submucosal dissection to prevent severe esophageal stricture in a porcine model

“…However, The rejection of transplanted allogeneic ECSs may not be observed within a week after the transplantation of allogeneic ECSs. In clinical settings, allogeneic tissue-engineered skin therapies provide biological dressings, matrix materials, cytokines, and regulatory molecules to maintain a suitable environment for wound healing without any immunological problems [ 50 , 51 ]. Moreover, the risk of immunological rejection can be minimized if the cell source for transplantation can be selected from a cell bank based on the human leukocyte antigen matching score, as in haplotype-based banking of human pluripotent stem cells [ 52 ].…”