Cell Stem Cell: Long-term profiling of wound regeneration

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Cell Stem Cell: Long-term profiling of wound regeneration

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Cell Stem Cell: Long-term profiling of wound regeneration.

Regeneration is the holy grail of tissue repair, but skin damage often produces fibrotic, non-functioning, ugly scars.

Therefore, how to promote regenerative therapy to remove scars formed after wound recovery requires a deep understanding of the molecular trajectory from injury to fibrosis to regeneration.

On January 31, 2022, the research group of Michael T. Longaker of Stanford University School of Medicine and the research group of Geoffrey C. Gurtner published an article in Cell Stem Cell . Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing .

A cellular multi-omics approach to characterize the molecular trajectories of scar and wound regeneration in the context of YAP inhibition.

After tissue damage, fibrosis occurs, utilizing non-functional connective tissue to ensure that the wound can heal as quickly as possible.

However, due to the lack of hairs and glands that normal skin has, there is no thermoregulation and barrier protection.

Fibrosis poses a huge medical burden, but there is currently no effective treatment, partly due to a lack of understanding of the underlying mechanisms of regeneration and fibrotic wound healing [1,2] .

Previous work by the authors has shown that blocking mechanotransduction with YAP inhibitors prevents fibroblast fibrosis and promotes fibroblast regeneration, a process in which dermal appendages such as hair follicles and glands recover normally and the extracellular matrix regenerates.

The structure is the same as that of uninjured skin and has similar elasticity [3] .

To gain an in-depth understanding of this process, the authors wish to monitor the entire process of injury repair, and therefore performed a multimodal dynamic analysis of fibrotic and regenerative wounds at the molecular and cytological levels.

A total of 7 time points were analyzed by the authors : uninjured skin, the second day after surgery (inflammation period) , the seventh day after surgery (fibroblast proliferation period) , the tenth day after surgery, and the fourteenth after surgery Day 21 (wound re-epithelialization, fibroblasts produce extracellular matrix) , 21st post-surgery, and 30th post-surgery (fibroblasts remodel extracellular matrix) .

The authors used a splint excision wound model, which prevents the rapid wound contraction typical of loose skin mice, allowing monitoring of the wound recovery process [4] , and then injected a YAP inhibitor or a buffer control into the wound surface. Wounds were subjected to long-term multimodal analysis (Figure 1) .

Figure 1 Workflow of long-term multimodal analysis of mouse wound skin

The wounds of the control group formed obvious fibrotic scars with dense, linearly arranged extracellular matrix fibers, while after YAP inhibitor treatment, the fibrotic density of the extracellular matrix was lower and the growth direction was more random.

In addition, this result was reconfirmed by YAP knockout, and the difference in treatment between the inhibitor and the control group was not due to off-target effects of the inhibitor.

Using scRNA-seq, proteomics, and extracellular matrix ultrastructural analysis, the authors have established maps describing wound dynamics, so the authors then hope to use these maps to analyze the molecular biology of the divergence between wound regeneration and fibrosis” junctions”, which blocks fibrosis before it occurs and guides the formation of tissue regeneration.

Analysis of single cells found that regenerative and fibrotic processes were not mutually exclusive, with regeneratively active cells present in scar wounds, but in the absence of, for example, YAP inhibitor treatment, pro-fibrotic molecules were more rapidly The response overrides regenerative activity, leading to the development of a fibrotic scar phenotype.

In addition, the authors also analyzed the composition of some cell subsets associated with wounds, mainly including two types and six types of myeloid cells and lymphocytes, but the authors found that the inhibitor treatment was compared with the control group.

The composition of the cells did not show much difference. Therefore, whether the scar phenotype occurs is not due to differences in immune cells, and the crux may still be mainly concentrated in fibroblasts.

So what genes determine this difference? The differentially expressed genes in the map established by the authors point to the Wnt signaling pathway, including Wnt target genes, antagonist genes, and an important regulator Trps1.

Previous studies have shown that Trps1 is a master regulator of the Wnt signaling pathway and is associated with the development, growth and proliferation of skin glands [5-7] .

Through knockout and overexpression experiments of Trps1, the authors confirmed that this gene is necessary and sufficient for wound regeneration.

Collectively, this work establishes a molecular, cellular, and protein map of wound regeneration in adult mammals by long-term multimodal analysis of wound regeneration following YAP inhibitor treatment for future research in skin wounds Blockade of regeneration and fibrotic scarring provides extensive research resources.

references

https://doi.org/10.1016/j.stem.2021.12.011

1. Foster, D.S., Januszyk, M., Yost, K.E., Chinta, M.S., Gulati, G.S., Nguyen, A.T., Burcham, A.R., Salhotra, A., Ransom, R.C., Henn, D., et al. (2021). Integrated spatial multiomics reveals fibroblast fate during tissue repair. Proc. Natl. Acad. Sci. USA 118, e2110025118.

2. Griffin, M.F., desJardins-Park, H.E., Mascharak, S., Borrelli, M.R., and Longaker, M.T. (2020). Understanding the impact of fibroblast heterogeneity on skin fibrosis. Dis. Model. Mech. 13, dmm044164.

3. Rinkevich, Y., Walmsley, G.G., Hu, M.S., Maan, Z.N., Newman, A.M., Drukker, M., Januszyk, M., Krampitz, G.W., Gurtner, G.C., Lorenz, H.P., et al. (2015). Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151

4. Foster, D.S., Januszyk, M., Yost, K.E., Chinta, M.S., Gulati, G.S., Nguyen, A.T., Burcham, A.R., Salhotra, A., Ransom, R.C., Henn, D., et al. (2021). Integrated spatial multiomics reveals fibroblast fate during tissue repair. Proc. Natl. Acad. Sci. USA 118, e2110025118

5. Fantauzzo, K.A., and Christiano, A.M. (2012). Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis. Development 139, 203–214

6. Fantauzzo, K.A., Kurban, M., Levy, B., and Christiano, A.M. (2012). Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis. PLoS Genet 8, e1003002.

7. Fantauzzo, K.A., Tadin-Strapps, M., You, Y., Mentzer, S.E., Baumeister, F.A., Cianfarani, S., Van Maldergem, L., Warburton, D., Sundberg, J.P., and Christiano, A.M. (2008b). A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala phenotype in mice. Hum. Mol. Genet. 17, 3539–3551.

Cell Stem Cell: Long-term profiling of wound regeneration.

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