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bioRxiv · 10.1101/2022.09.24.509317

A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation

Lothstein, K. E.·Chen, F.·Mishra, P.·Smyth, D. J.·Wu, W.·Lemenze, A.·Kumamoto, Y.·Maizels, R. M.·Gause, W. C.
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Abstract

Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-{beta} mimic (TGM), an ES molecule secreted by Heligmosomoides polygyrus (Hp), binds TGF-{beta} receptors yet lacks structural homology to TGF-{beta} and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in an in vivo wound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. This included enhanced early accumulation and persistence of macrophages in TGM-treated wounds during the initial inflammatory phase. Additionally, the percentage of alternatively activated (M2) macrophages expressing CD206 was reduced with TGM treatment during early and mid-stage wound healing. scRNAseq analysis of TGM-treated wounds indicate upregulation of multiple wound healing-associated genes without expression of CD206 within macrophage subsets. Experiments with truncated TGM constructs revealed that the TGF{beta}-R binding domain was essential in enhancing the wound healing response. In summary, TGM can accelerate skin wound healing and pro-restorative maturation through its interaction with the TGF-{beta} receptor and stimulate the recruitment and reprogramming of specific macrophage subsets. This study indicates a role for TGM as a potential novel therapeutic option for enhanced wound healing. One-Sentence SummaryA helminth-derived protein leads to rapid wound closure, skin regeneration, and reprogramming of macrophage activation through TGF-{beta}R binding.

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Lothstein, K. E., Chen, F., Mishra, P., Smyth, D. J., Wu, W., Lemenze, A., Kumamoto, Y., Maizels, R. M., Gause, W. C.. 2022-09-25. A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation. https://doi.org/10.1101/2022.09.24.509317

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