Mechanisms and Treatments of Fibrosis

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very intriguing data! It would be nice to see how exactly the replicates lined up on Single-cell RNA-seq and multi-omics 3 x ?

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interesting point! look at the F1B vs. 1C. the velvet has no blood. would that be the reason as well?

other than the difference of the fibroblasts as authors highlighted, tissue structures are very distinct between back skin and velvet, the former appears looser but more blood vessels than the latter in subcutaneous tissue.

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Wound healing mechanisms and specific cell functions in wound repair have been studied in wide extent. It’s the distinct interplay of different cells and mediators. The transition from the inflammatory to the proliferative stage of wound repair is crucial in regeneration vs. scar formation.
In contrast to fetal wound repair, normal adult skin wound healing results in a collagenous scar. In scarless fetal wounds, the epidermis and dermis are restored to a normal architecture. The collagen dermal matrix pattern is reticular and unchanged from unwounded dermis. The wound hair follicle and sweat gland patterns are normal as well. The mechanisms are currently poorly understood. Fibroblasts certainly play crucial roles in response to pro-fibrotic mediator, e.g. TGF-β…
Above studies of fibroblast-immune interactions in Reindeer is quite promising, and may shed light to the field.


thanks all for discussion

So the interactions between nature of skin fibroblasts and local tissue (environment) determine fate of skin recovery from wound (regeneration and scar formation). Ectopic transplantation of velvet to scar-forming back skin didn’t work out due to the uncared problems from environmental part. It’d be more studies on local tissues to support or facilitate regeneration along with good fibroblasts.


This report highlighted a mechanotransduction inhibitor - verteporfin yielding to wound regeneration, in which Trps1 appeared to be a key driving force on fibroblasts. The verteporfin wound fibroblasts seemed like pro-regenerative fibroblasts.
It is in contrast to the above paper (top) that highlighted fibroblast-immune interactions, and the importance of the inflammatory primed fibroblasts to scar formation in wound healing.

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both papers didn’t talk much on myofibroblasts, which can enhance inflammatory response, and they are profibrotic.


The studies of skin scar vs fibrosis in other organs are some in common, but bit of different. It’d be nice to see how these studies on skin scar applied into other fibrosis, e.g. pulmonary and hepatic fibrosis.


an investigator-initiated clinical trial (human study) indicated that CD8+ T cell population is capable of TCR-independent hepatocyte killing.

Electrospun nanofibers impregnated with different biological macromolecules for wound healing

By combining these two papers (1.Macrophages directly contribute collagen… 2.Distinct fibroblast progenitor subpopulation …), we can learn that macrophages and fibroblasts both play a role in the healing process after an injury. Macrophages are involved in extracellular matrix turnover and activating cardiac fibroblasts to initiate collagen deposition, while Prx1+ cells are a critical fibroblast subpopulation that expedites mucosal healing by facilitating early immune response. Both macrophages and Prx1+ cells may contribute to wound healing by differentiating into immunomodulatory SCA1+ fibroblasts, which prime macrophage recruitment through CCL2.

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The seven papers above all discuss on the mechanisms of fibrosis and the potential for interventions to mitigate its effects.

The first paper discusses the difference in wound healing between reindeer antler skin and back skin, and how this difference is related to the immune response of the skin fibroblasts. The paper concludes that the reindeer antler skin regenerates, whereas the back skin forms a fibrotic scar, and suggests that decoupling fibroblast-immune interactions may be a promising approach to mitigate scarring.

The second paper describes the molecular events driving skin wound cells towards scarring or regenerative fates. The paper concludes that disrupting YAP mechanotransduction yields regenerative repair by fibroblasts with activated Trps1 and Wnt signaling, and that Trps1 is a key regulatory gene that is necessary and partially sufficient for wound regeneration.

The third paper examines the effects of metformin, a widely used antidiabetic drug, on fibrosis. The paper concludes that metformin is able to reduce/modulate the expression of different actors involved in fibrosis, and that it controls the expression of several key TGF/Smad factors and four major fibrogenic MMPs.

The fourth study reveals that macrophages directly contribute to collagen deposition in the formation of post-injury scar, in contrast to the current understanding that collagen deposition is exclusively attributed to myofibroblasts. This finding implicates macrophages as direct contributors to fibrosis during heart repair.

The fifth study identifies a specific subpopulation of fibroblasts, postnatal paired-related homeobox-1+ (Prx1+) cells, as critical to the regenerative capacity of the oral mucosal barrier. These cells facilitate early immune response and accelerate wound healing, suggesting that Prx1+ fibroblasts may be a valuable source for regenerative procedures for the treatment of corneal wounds and enteropathic fibrosis.

The sixth study uses longitudinal liver sampling and single-cell sequencing to investigate the underlying mechanisms of fibrosis in chronic hepatitis B. The study identifies a distinct liver-resident, polyclonal CD8+ T cell population that drives pathogenesis and identifies a key pathway involved in its function in CHB patients.

The seventh study highlights the global epidemic of non-healing infected wounds and the limitations of current commercial wound therapies in promoting tissue re-epithelialization. The study proposes the use of nanomaterial-based drug delivery systems as a potential solution to these issues.

A conclusion from these studies is that fibrosis is a complex process that is influenced by a variety of factors, including the immune response of fibroblasts, (e.g. subpopulation of fibroblasts and macrophages), the molecular events driving skin wound cells towards scarring or regenerative fates, interventions targeting specific cell populations and pathways may be effective in mitigating fibrosis. Perspective future studies may involve further exploration of these specific cell populations and pathways, as well as the development and testing of potential interventions in preclinical and clinical settings.


CTGF regulates extracellular matrix (ECM) production and its elevated levels have been found in multiple fibrotic disease patients and in animal models. Using a 3D human liver co-culture spheroid model, researchers induced fibrosis with TGF-β1, CTGF or free fatty acids (FFA) and found that treatment increased COL1A1 deposition and expression of TGF-β1 and CTGF. CTGF and IL-6 were found to play a role in liver inflammation and fibrosis in the human 3D liver spheroid model.

  • The study investigates the role of fibroblast-specific protein 1 (FSP-1) positive cells in kidney fibrosis during a kidney injury.
  • The researchers found that FSP-1 positive cells in the obstructed kidneys of mice are mostly bone marrow-derived inflammatory cells (macrophages).
  • They also discovered that the Notch signaling pathway plays a role in activating these cells and producing M1 cytokines, which are important for renal inflammation and fibrosis.
  • Inhibiting Notch signaling suppressed the activation and cytokine secretion of FSP-1+ cells, reducing ECM deposition, the infiltration of FSP-1+ inflammatory cells, and cytokine production, ultimately alleviating myofibroblast accumulation and kidney fibrosis.