In VitroandEx VivoModels for Functional Testing of Therapeutic Anti-scarring Drug Targets in Keloids

Abstract

Keloids are benign fibro-proliferative raised dermal lesions that spread beyond the original borders of the wound, continue to grow, rarely regress, and are the most common in pigmented individuals after an abnormal wound healing response. The current treatment failure and respective challenges involved highlighting the underlying issue that the etiopathogenesis of keloids is still not well understood. Disease models are required to better understand the disease pathogenesis. It is not possible to establish keloids in animals because of the uniqueness of this disease to human skin. To address this challenge, along these lines, non-animal reproducible models are vital in investigating molecular mechanisms of keloid pathogenesis and therapeutics development. Recent Advances: Various non-animal models have been developed to better understand the molecular mechanisms involved in keloid scarring and aid in identifying and evaluating the therapeutic potential of novel drug candidates. In this scenario, the current review aims at describing in vitro monocultures, co-cultures, organotypic cultures, and ex vivo whole skin keloid tissue organ culture models. Critical Issues and Future Directions: Current treatment options for keloids are far from securing a cure or preventing disease recurrence. Identifying universally accepted effective therapy for keloids has been hampered by the absence of appropriate disease model systems. Animal models do not accurately mimic the disease, thus non-animal model systems are pivotal in keloid research. The use of these models is essential not only for a better understanding of disease biology but also for identifying and evaluating novel drug targets.

Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3

“…While the use of commercial cell lines may afford other researchers an opportunity to reproduce and expand upon our findings, our results cannot address the likely person-to-person, or body site-to-body site variation in healthy donors or patients with keloids. Full elucidation of keloid metabolism may also need to employ additional models and/or evaluate pathology in keloid-derived keratinocytes and melanocytes [44]. Furthermore, while our findings reproduce the findings of prior reports identifying JAK1/2, STAT3, and folate as targetable pathways for the treatment of keloids, a potentially contrasting role for vitamin D impacting STAT3 signaling and risk of keloids in pigmented skin should also be considered [34,45].…”

Immune cells and associated molecular markers in dermal fibrosis with focus on raised cutaneous scars

“…Keloid therapy most often targets hyperactive fibroblast proliferation to halt increased amount of collagen deposition, 24,26 and to induce shrinkage of the keloid lesion 27–29 . The effect of therapeutic compounds against HTS, KD, and FKN dermal scars can be investigated using several models and assays including investigating keloid derived fibroblast proliferation, migration and invasion, in order to evaluate the effect of potential anti‐fibrotic candidates 30,31 . The high recurrence rate that often occurs post‐conventional therapies is a clinical challege and a major cause to intensify research for identifying better therapies with minimal side effects and reduced recurrence rates.…”

“… 27 , 28 , 29 The effect of therapeutic compounds against HTS, KD, and FKN dermal scars can be investigated using several models and assays including investigating keloid derived fibroblast proliferation, migration and invasion, in order to evaluate the effect of potential anti‐fibrotic candidates. 30 , 31 The high recurrence rate that often occurs post‐conventional therapies is a clinical challege and a major cause to intensify research for identifying better therapies with minimal side effects and reduced recurrence rates. Current treatment approaches include topical anti‐scarring application, surgical excision, cryotherapy, pressure dressing, laser therapy, intralesional corticosteroid injections, and antimetabolites.…”

WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis

“…Keloids only occur in humans, making it difficult to study disease pathogenesis [ 32 ]. Currently available potential keloid animal models involve keloid reproduction either by chemical-induced abnormal fibrosis or implantation of human keloid tissues [ 33 ].…”