The human umbilical cord–mesenchymal stem cell secretome regulates hair growth and cycle transition by promoting methylthioadenosine synthesis via the PI3K/AKT/mTOR pathway

Abstract

Background The human umbilical cord (hUC)–mesenchymal stem cell (MSC) secretome (SCT) is a cell-free therapy that may emerge as a novel therapeutic strategy for hair loss prevention. Here, we aimed to elucidate the underlying mechanisms through which SCT regulates hair growth and cycle transition. Methods Using C57BL/6 mice, ex vivo follicles, and cell experiments, we studied the effects and mechanisms of SCT on hair growth and cycling using untargeted metabolomics and phosphoproteomics. A three-month double-blind clinical study was conducted to validate the effects of SCT on human hair. Results SCT promotes the telogen-to-anagen transition, hair thickening, and elongation of the vibrissae in mice; regulates dermal papilla cells and hair matrix cells through cysteine and methionine metabolism; and stimulates methylthioadenosine synthesis in hair matrix cells by activating the PI3K/AKT/mTOR signaling pathway. Clinical studies demonstrated that SCT increased human hair density and average hair diameter. Scalp physiological tests and subjective feedback indicated no related adverse reactions on the scalp or hair. Conclusions SCT promoted hair growth, thickening, and the hair follicle cycle via the PI3K/AKT/mTOR signaling pathway. This research provides a basis for the application of cell-free alternatives in hair care and hair loss prevention.

1. Introduction

Hair loss is a global problem that is becoming increasingly common, particularly among younger individuals. However, existing hair loss treatments, which include oral and topical drugs, hair transplants, and emerging platelet-rich plasma, often do not meet patient expectations [1]. Therefore, other anti-hair loss interventions should be explored.

Hair is produced by hair follicles, specialized accessory organs of the skin, which consists of the epithelium and dermis. These follicles exhibit self-renewal and maintain a regular cycle of hair growth, shedding, and regeneration. The hair follicle cycle in the scalp comprises three stages: anagen, catagen, and telogen [2]. During this cycle, the upper one-third of the hair follicle structure remains stable, with only the lower two-thirds, which includes the root, hair bulb (Hb), and dermal papilla at the bottom of the Hb, undergoing cyclic changes. Dermal papilla cells (DPCs) are a type of mesenchymal cell with pluripotent stem cell characteristics [3, 4]. Following the laser ablation of DPCs, hair follicles cannot re-enter the anagen phase [5]. Moreover, DPCs in the hair loss area exhibit a senescent phenotype, in which hair follicles also remain in the telogen phase [6]. These findings indicate that signals from DPCs, which serve as a signal-modulating center [7], can induce hair follicles to transition from the telogen to the anagen phase. In this process, hair follicle stem cells proliferate and differentiate into hair matrix cells (HMCs), which continue to proliferate, migrate, and regenerate the lower two-thirds of the hair follicle structure. During this period, close molecular signal communication between HMCs and DPCs effectively regulates the periodic regeneration of some hair follicle structures [8]. A decreased proliferation ability of HMCs affects the hair cycle, hair regeneration [9], and hair elongation [10]. Thus, maintaining and regulating DPC and HMC activity is of great significance for hair growth and regeneration and in the prevention of hair loss.

Hair-regenerative medicine represents a promising treatment for hair loss. Specifically, the human umbilical cord–mesenchymal stem cell (hUC-MSC)-derived secretome (SCT) is a cell-free therapy that offers a novel approach to the prevention and treatment of hair loss [11]. SCT refers to substances secreted by stem cells in the extracellular space through known or unknown secretion mechanisms under specific conditions and includes soluble proteins, free nucleic acids, lipids, extracellular vesicles, apoptotic bodies, and part...