Senolytics Boost Hair Growth in Skin Grafts

In a recent study published in Aging Cell, researchers have unveiled promising methodologies for enhancing hair growth through a novel approach of mitigating cellular senescence. This advancement represents a significant milestone towards developing effective hair-growing skin grafts.

The Quest for a True Stem Cell Hair Treatment

Historically, efforts to restore hair follicle growth have revolved around the utilization of dermal papilla cells (DPs), which are recognized as the mesenchymal stem cells responsible for promoting hair growth within follicles [1]. However, achieving clinical success with DPs has proven challenging: these cells often lose their functional abilities outside of their native microenvironment within active hair follicles [2]. Furthermore, repeated cultivation of human DPs results in a decrease in their regenerative capacity. Despite various attempts to rejuvenate these cells through methods like conditioned media [3] and extracellular matrix scaffolds [4], such strategies have only shown efficacy with early-passage cells.

One of the primary causes attributed to this decline in capability is an increase in cellular senescence. Both senescent cells and their secretory products, collectively known as the senescence-associated secretory phenotype (SASP), have been implicated in cellular dysfunction [5]. Notably, experiments have demonstrated that the removal of senescent cells can lead to hair regeneration in mouse models [6].

Hair Cells Become Senescent Quickly in Culture

In their foundational experiment, the researchers isolated and cultured DPs alongside dermal fibroblasts (DFs) from the same donor. Although DFs do not promote hair growth, they are extensively studied regarding senescence and are a common progenitor for DPs.

The data revealed that DPs exhibited a more rapid onset of senescence compared to DFs, beginning at the very first passage as indicated by the well-known biomarker SA-β-Gal. Additional senescence markers such as a loss of proliferative capacity and an increase in p16 and p21 further corroborated this observation. The increase in senescence was also paralleled by a significant elevation in SASP factors including inflammatory cytokines IL-6 and IL-8. Moreover, exposure to these inflammatory factors resulted in the suppression of the productive abilities of surrounding non-senescent cells.

A Senolytic Solution

Senolytics, a class of drugs designed to selectively induce death in senescent cells, present a possible solution in cell culture settings where traditional concerns regarding their application do not apply. The researchers administered a combination of dasatinib and quercetin, established senolytics, to DPs at their third passage. This treatment achieved success in rapidly eliminating senescent cells from the DP population.

Notably, many surviving cells transitioned into a quiescent state, as indicated by the biomarker p27. Quiescent DPs, unlike senescent counterparts, retain the ability to be stimulated to fulfill their intended functions. Furthermore, the senolytic treatment significantly diminished the influence of the SASP, resulting in a dramatic reduction of inflammatory factors like IL-6.

Experimental Results

The researchers further explored the implications of their findings by creating 500 spheroids composed of 2000 human DPs and 1 million mouse keratinocytes, implanted into the dorsal regions of hairless mice. The results highlighted a remarkable difference in hair growth efficacy between the senolytic treatment group and control, with earlier-passage DPs demonstrating superior growth outcomes compared to those from later passages.

These observations were validated in experiments involving cultured human skin, where a mixture of one million human DPs and two million human DFs seeded in collagen wells demonstrated superior hair follicle and keratin structure formation when exposed to senolytics, contrasting starkly with the control group.

Conclusion and Future Directions

While the researchers acknowledge that their study is a work in progress and that an immediate solution for hair loss is still elusive, they contend that targeting senescence through senolytics is a pivotal strategy to overcome significant barriers in hair regenerative medicine. Further investigations will be needed to develop artificial human skin capable of eliciting hair growth comparable to normal, healthy human conditions.

Support for such research is paramount as the quest for effective hair regeneration continues.

Literature Cited

[1] Leirós, G. J., et al. (2014). Dermal papilla cells improve the wound healing process and generate hair bud-like structures in grafted skin substitutes using hair follicle stem cells. Stem Cells Translational Medicine, 3(10), 1209-1219.

[2] Ohyama, M., et al. (2012). Restoration of the intrinsic properties of human dermal papilla in vitro. Journal of Cell Science, 125(17), 4114-4125.

[3] Abreu, C. M., et al. (2021). Rescuing key native traits in cultured dermal papilla cells for human hair regeneration. Journal of Advanced Research, 30, 103-112.

[4] Liu, Z., et al. (2023). Microenvironmental reprogramming of human dermal papilla cells for hair follicle tissue engineering. Acta Biomaterialia, 165, 31-49.

[5] Shin, W., et al. (2020). Dysfunction of hair follicle mesenchymal progenitors contributes to age-associated hair loss. Developmental Cell, 53(2), 185-198.

[6] Baar, M. P., et al. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.

[7] Lifespan.io