Abstract
Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti–hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ.
Highlights
In recent years, autophagy has emerged as a pivotal actor in adaptive responses to stress and starvation [1,2,3] and in tissue homeostasis [4], cellular differentiation [5], and ageing [6,7]
Human scalp hair follicles (HFs) experience a massive growth for years, until they spontaneously enter into a rapid, apoptosis-driven organ involution process, orchestrated by an organ-intrinsic “hair cycle clock,” the molecular control of which remains unclear
We find that genetic inhibition of follicular autophagy induces premature catagen and enhances hair matrix keratinocyte apoptosis, suggesting that autophagic flux in the anagen hair matrix is important for the maintenance of this stage
Summary
Autophagy has emerged as a pivotal actor in adaptive responses to stress and starvation [1,2,3] and in tissue homeostasis [4], cellular differentiation [5], and ageing [6,7]. It would be helpful to have an tractable, clinically relevant human organ model at our disposal Such human models would be useful to assess the efficacy and safety of the ever-increasing number of strategies that are being proposed to therapeutically modulate autophagy to treat various human diseases and to slow tissue ageing [9,10,11,12]. On this background, we have turned to a complete, cyclically remodelled human (mini-) organ, i.e., terminal scalp hair follicles (HFs) [13]. Under these conditions, growing (anagen) HFs continue to produce a pigmented hair shaft and will continue their spontaneous organ remodelling activity for many days ex vivo
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