Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing

Abbasi, Sepideh; Sinha, Sarthak; Labit, Elodie; Rosin, Nicole L.; Yoon, Grace; Rahmani, Waleed; Jaffer, Arzina; Sharma, Nilesh Kumar; Hagner, Andrew; Shah, Prajay; Arora, Rohit; Yoon, Jessica L.; Islam, Anowara; Uchida, Aya; Chang, Chung Pai; Stratton, Jo Anne; Scott, R. Wilder; Rossi, Fábio; Underhill, T. Michael; Biernaskie, Jeff

doi:10.1016/j.stem.2021.02.004

Cited by 34 publications

(51 citation statements)

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“…Increased fibroblast proliferation within permissive wound environments can also be associated with enhanced regeneration, further suggesting that fibroblast overabundance alone is not a key determinant of fibrosis. 117 Fibroblast-derived fibrillar collagen gradually replaces fibrin, and collagen remodeling by fibroblast traction and contraction forces confers strength to the wound. This fibroblast activation stage is hallmarked by neo-formation of cytoplasmic stress fibers and often referred to as proto-myofibroblast (Figure 3).…”

Section: Fibroblast-to-myofibroblast Activation During Skin Healing and Pathologymentioning

confidence: 99%

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Sawant

Hinz

Schönborn

et al. 2021

Wound Repair Regeneration

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Our skin is continuously exposed to mechanical challenge, including shear, stretch, and compression. The extracellular matrix of the dermis is perfectly suited to resist these challenges and maintain integrity of normal skin even upon large strains. Fibroblasts are the key cells that interpret mechanical and chemical cues in their environment to turnover matrix and maintain homeostasis in the skin of healthy adults. Upon tissue injury, fibroblasts and an exclusive selection of other cells become activated into myofibroblasts with the task to restore skin integrity by forming structurally imperfect but mechanically stable scar tissue. Failure of myofibroblasts to terminate their actions after successful repair or upon chronic inflammation results in dysregulated myofibroblast activities which can lead to hypertrophic scarring and/or skin fibrosis. After providing an overview on the major fibrillar matrix components in normal skin, we will interrogate the various origins of fibroblasts and myofibroblasts in the skin. We then examine the role of the matrix as signaling hub and how fibroblasts respond to mechanical matrix cues to restore order in the confusing environment of a healing wound.

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Section: Fibroblast-to-myofibroblast Activation During Skin Healing and Pathologymentioning

confidence: 99%

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Sawant

Hinz

Schönborn

et al. 2021

Wound Repair Regeneration

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“…Following isolation, the expression of fibroblast markers dlk1 , dpp4 , pdgfra , and thy1 were assessed (Figure S2). Expression of dlk1 and dpp4 have been utilized to differentiate between previously identified fibroblast subsets, whereas pdgfra and thy1 have been observed to be widely expressed across fibroblast populations 2,3,11‐13 . Notably, cell lineage did not significantly affect the expression of any of these genes ( p > 0.05).…”

Section: Resultsmentioning

confidence: 99%

“…During development, the most dorsal fibroblast population, characterized by the expression of blimp1 and lrig1 , gives rise to the papillary dermal fibroblasts of postnatal mice 3 . In contrast, the more ventral population, expressing dlk1 , contributes to the reticular dermal fibroblasts and underlying adipogenic populations 3,11 . Furthermore, lineage tracing analysis of these populations identified their unique contributions to dermal wound repair in adult mice.…”

Section: Introductionmentioning

confidence: 99%

Lineage tracing of Foxd1‐expressing embryonic progenitors to assess the role of divergent embryonic lineages on adult dermal fibroblast function

2021

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Recent studies have highlighted the functional diversity of dermal fibroblast populations in health and disease, with part of this diversity linked to fibroblast lineage and embryonic origin. Fibroblasts derived from foxd1-expressing progenitors contribute to the myofibroblast populations present in lung and kidney fibrosis in mice but have not been investigated in the context of dermal wound repair. Using a Cre/Lox system to genetically track populations derived from foxd1-expressing progenitors, lineage-positive fibroblasts were identified as a subset of the dermal fibroblast population. During development, lineage-positive cells were most abundant within the dorsal embryonic tissues, contributing to the developing dermal fibroblast population, and remaining in this niche into adulthood. In adult mice, assessment of fibrosis-related gene expression in lineage-positive and lineage-negative populations isolated from wounded and unwounded dorsal skin was performed, identifying an enrichment of transcripts associated with matrix synthesis and remodeling in the lineage-positive populations. Using a novel excisional wound model, ventral skin healed with a Accepted Article greatly reduced frequency of foxd1 lineage-positive cells. This work supports that the embryonic origin of fibroblasts is an important predictor of fibroblast function, but also highlights that within disparate regions, fibroblasts of different lineages likely undergo convergent differentiation contributing to phenotypic similarities.

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“…ey can adapt to the environment and perform different functions through metabolic remodeling in different tissues [23]. In the wound healing process, tissue microenvironment changes are characterized by hypoxia and competition for nutrients by large numbers of infiltrating cells, forcing the immune cells to adapt to the microenvironment by reprogramming their metabolism [24,25]. Lipopolysaccharides and other substances secreted by pathogens activate M1 macrophages, which use aerobic Evidence-Based Complementary and Alternative Medicine glycolysis to produce energy and molecules for biosynthesis, thus, increasing the flux through PPP to allow NADPH to produce reactive oxygen species (ROS) [26].…”

Section: Discussionmentioning

confidence: 99%

Production of an Animal Model of Semi-Yin and Semi-Yang Syndrome with Diabetic Ulcers and Study of Its Pathological and Metabolic Features

Liu

Shi

Xiong

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. To create an animal model for diabetic ulcers with semi-Yin and semi-Yang (SYSY) syndrome and to study the pathological and metabolic features of SYSY syndrome. Methods. Firstly, based on the clinical characteristics of the SYSY syndrome of diabetic ulcer, an animal model of diabetic ulcers with SYSY syndrome being full-thickness skin defects was created by injecting streptozotocin (STZ) intraperitoneally, infecting with Staphylococcus aureus, and gastrically administering senna. Secondly, the content and distribution patterns of collagen fibers, the expression of neutrophils and macrophage markers, angiogenesis, and the expression of IL-1β and IL-10 in the rats with Yang syndrome, Yin syndrome, and SYSY syndrome of diabetic ulcers at different time points were detected. Representative traditional Chinese medicine (TCM) ointment of Yang syndrome, Yin syndrome, and SYSY syndrome was used to treat this animal model. The above indexes in each treatment group were detected. Finally, metabonomics was used to detect and analyze the changes of differential metabolites related to macrophage metabolism in Yang, Yin, and SYSY syndromes at different time points. Results. An animal model of diabetic ulcers with SYSY syndrome was established. The pathological features of the SYSY syndrome group were chronic low-grade inflammatory reactions. On the third day, the SYSY syndrome group displayed lower expression of CD16, CD68, CD163, IL-1β, and metabolites related to M1-type macrophages compared with other groups. On the seventh day, the SYSY syndrome group showed lower expression of CD31, IL-10, myeloperoxidase, and metabolites related to M2-type macrophages. Treatment with Chong He Ointment, a representative TCM ointment for SYSY syndrome, reversed the expression levels of these indexes and promoted wound healing in the SYSY group. Conclusion. SYSY syndrome presents a persistent pathological state of low inflammation, which may be caused by an insufficient activation of the M1-type metabolic pathway in macrophages in the early acute inflammatory stage, resulting in the incomplete clearance of pathogens and debris and continuous stimulation of macrophages to initiate the M1-type metabolic pathway. CD163, CD31, IL-10, and citric acid can be used as potential specific markers for the recovery and progression of SYSY syndrome.

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Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing

Cited by 34 publications

References 0 publications

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Lineage tracing of Foxd1‐expressing embryonic progenitors to assess the role of divergent embryonic lineages on adult dermal fibroblast function

Production of an Animal Model of Semi-Yin and Semi-Yang Syndrome with Diabetic Ulcers and Study of Its Pathological and Metabolic Features

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