Pooja Pathak

Background: The skin is the largest organ of the human body and acts as our first line of defense against the plethora of pathogens and external environmental factors we face every day–for this reason it’s also especially susceptible to wounds and scarring¹. Patients who have suffered from burns, traumatic injuries, congenital skin disorders, skin cancers, surgical procedures, etc. deal with impaired skin function and integrity which presents them with a very serious health challenge. Current techniques involving skin transplantation come with the high risk of rejection, scarcity of donor sites, and high incidence of infections¹.This technique activates the immune system and alerts it to the foreign body present. This happens with macrophages, dendritic cells, cytokines, etc infiltrating the graft. Simultaneously, the dendritic cells from the donor migrate to the recipient’s lymphoid organ system and present the donor antigens, which enables an adaptive immune response to occur. The T cells then become activated and proliferate, secreting cytokines and infiltrating the graft where they kill the donor cells, thereby rejecting the graft².

Objective:In this narrative review, I explored the mechanisms by which induced pluripotent stem cells, vascularization, hair appendages, and innervation bettered human skin construct models for more efficient testing of disease progression, drug testing, and cosmetic skin product testing.

Search Methods: An online search on the PubMed database was conducted from the years 2018-Present using the following keywords “Skin-construct,” “Tissue engineering,” “Skin organoid models,” and “skin transplantation.”

Results: It was shown that capacity of adult and hiPSC-derived skin cell types to self-organize into organoid structures in vitro and regenerate functional, vascularized human skin-like tissue upon transplantation was possible with the presence of endothelial colony forming cells (ECFCs) and human platelet lysate (hPL).³ Additionally, using prevascularized dermal constructs enhanced the skin healing process by implementing growth factors such as endothelial growth factor (EGF) and vascular endothelial growth factor (VEGF) which facilitated processes such as angiogenesis and promoted anastomosis with host vasculature.⁴ Furthermore, studies showed that overexpression of Lef1 increased expression of keratin lineage markers (K17, K71, K25, K75) which enhanced efficiency of hair follicle induction.⁵ Lastly, differentiation of human induced pluripotent stem cells to induce innervation was compared to human fetal skin samples and showed close proximity to the morphology and function via its marker expression.⁶

Conclusions: Overall, the studies show that a compilation of these efforts to add factors important to skin regeneration can have an impactful effect on mimicking the function of real skin. Factors such as CRABP1, Lef1, and MDK were identified to have regenerative capabilities in a clinical trial approach and offer possibilities of how to strengthen skin organoid models in the future. ⁷

Works-Cited:

1. Weng T, Zhang W, Xia Y, et al. 3D bioprinting for skin tissue engineering: Current status and perspectives. J Tissue Eng. 2021;12:20417314211028574. Published 2021 Jul 13. doi:10.1177/20417314211028574
2. ​​Leonard, D.A., Amin, K.R., Giele, H. et al. Skin Immunology and Rejection in VCA and Organ Transplantation. Curr Transpl Rep 7, 251–259 (2020). https://doi.org/10.1007/s40472-020-00310-1
3. Ebner-Peking P, Krisch L, Wolf M, et al. Self-assembly of differentiated progenitor cells facilitates spheroid human skin organoid formation and planar skin regeneration. Theranostics. 2021;11(17):8430-8447. Published 2021 Jul 25. doi:10.7150/thno.59661
4. Mazio C, Mavaro I, Palladino A, et al. Rapid innervation and physiological epidermal regeneration by bioengineered dermis implanted in mouse. Mater Today Bio. 2024;25:100949. Published 2024 Jan 10. doi:10.1016/j.mtbio.2024.100949
5. Abaci HE, Coffman A, Doucet Y, et al. Tissue engineering of human hair follicles using a biomimetic developmental approach. Nat Commun. 2018;9(1):5301. Published 2018 Dec 13. doi:10.1038/s41467-018-07579-y
6. Lee J, Rabbani CC, Gao H, et al. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature. 2020;582(7812):399-404. doi:10.1038/s41586-020-2352-3
7. Sinha S, Sparks HD, Labit E, et al. Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer. Cell. 2022;185(25):4717-4736.e25. doi:10.1016/j.cell.2022.11.004