Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages

Abstract

Skin allo- and xenotransplantation are the standard treatment for major burns when donor sites for autografts are not available and have been shown to significantly accelerate wound healing. Although the cellular elements of foreign grafts are rejected, the extracellular matrix components integrate into the wound and may underlie their beneficial effects on wound healing. The molecular mechanisms defining the relationship between the immune response to foreign grafts and their impact on wound healing have not been fully elucidated. Here, we investigated changes in collagen architecture after xenogeneic implantation of clinically available human biologic scaffolds. We show that collagen deposition in response to the implantation of human split-thickness skin grafts (hSTSG) containing live cells recapitulates normal skin architecture, whereas human acellular dermal matrix (ADM) grafts led to highly aligned collagen deposition, characteristic of fibrosis and scar. Using single-cell RNA-sequencing, we show that macrophage differentiation in response to hSTSG is driven by vitamin D (VD) signaling toward Trem2+ subpopulations with an enrichment of pro-angiogenic and anti-fibrotic transcriptomic programs. We subsequently induced this regenerative subpopulation in vitro by treating bone marrow-derived cells with vitamin D3 and found that hydrogel delivery of Trem2+ macrophages significantly accelerated wound closure in a human-like murine excisional wound model. Our study identifies the preclinical therapeutic potential of Trem2+ macrophages to mitigate fibrosis and promote wound healing and provides a novel effective strategy to develop advanced cell therapies for complex wounds.

Photothermal Controlled‐Release Immunomodulatory Nanoplatform for Restoring Nerve Structure and Mechanical Nociception in Infectious Diabetic Ulcers

“…Trem2 + macrophages promote bacterial clearance, collagen remodeling, and full-thickness skin regeneration during wound healing. [28,63] Here, it was demonstrated that the recruitment of Trem2 + macrophages on Day 3 was statistically higher in the pGel/M-NIR and MpGel-NIR groups, and the MpGel-NIR group maintained this increase on Day 28, indicating the beneficial recruitment of macrophages by pGO. (Figure 5A,B,E,F and Figure S13, Supporting Information).…”

“…The recruitment of Trem2 + macrophages regulates collagen remodeling and promotes angiogenesis. [28] Damaged endothelial progenitor cells and low cytokines limit angiogenesis in diabetic wounds. [67] Moreover, pathological angiogenesis can result in functional ischemic wounds.…”

“…deposition. [28,29,62] With the advancement of single-cell sequencing technology, the classification of macrophages is no longer limited to M1 and M2, but classified into subpopulations according to function or gene expression, allowing for a more precise understanding of their activity. Therefore, instead of detecting the M2 phenotype, it is vital to also ensure that the beneficial subpopulation is recruited.…”

“…[17] Vascular Endothelial Growth Factor (VEGF), the most common angiogenic agent, promotes infection and inflammation, which hinders infectious wound healing. [26] On the other hand, angiogenesis may be accelerated by inducing an appropriate immune response, [27,28] increasing long-term vascular regeneration, and reducing the risk of VEGF-induced infection. However, common pharmacological or biological immunomodulators can cause systemic immunological disorders.…”

Immune micro-environment around biomaterials implanted in soft tissues: emerging analytical techniques and advancements in modulation

“…Using scRNA-seq, they found a distinct subpopulation of macrophages with a high expression of the lipid receptor Trem2 (triggering receptor expressed on myeloid cells), which demonstrated the great effectiveness in alleviating wound repair. [73] Similarly, in the study by Sommerfeld et al, murine volumetric muscle injuries received treatment with ECM or synthetic biomaterial. CD45 + CD64 + F4/80 hi+ macrophages were sorted for single cell analysis.…”