Tissue regeneration is a complex process that involves the coordinated efforts of adult stem cells and their microenvironment. Mechanical forces play a crucial role in regulating cellular behavior, including cell adhesion, division, migration, and differentiation. However, the direct observation of how mechanical forces affect stem cell activity and tissue regeneration has been challenging.
In a recent study, researchers have made significant strides in understanding the role of mechanical properties in hair follicle stem cells (HF-SCs) and hair growth. By examining the mechanical properties of different cell populations within the HF-SC niche, they shed light on the spatiotemporal regulation of mechanical forces in tissue regeneration.
As per PNAS, mammalian skin, particularly hair follicles, provides an excellent experimental model to investigate the influence of mechanical mechanisms on stem cell activity, tissue regeneration, wound repair, and even tumorigenesis. Researchers have previously discovered that a subset of epidermal stem cells responds to external force-induced stretch by transiently activating cell division.
Perturbations in the force-generating cytoskeleton and extracellular matrix have been shown to compromise tissue functions. Understanding how mechanical forces affect the transition between quiescence and activation of HF-SCs and their progenitors is of great interest.
In this study, researchers unraveled the spatiotemporal compartmentalization of mechanical properties within the HF-SC niche. They found that bulge HF-SCs, which are responsible for hair regeneration, exhibit stiffness and strong actomyosin contractile forces. On the other hand, hair germ (HG) progenitor cells, which initiate hair growth, are relatively soft and mechanically dynamic.
These distinct mechanical properties suggest that HG progenitor cells are more sensitive to changes in mechanical forces, enabling them to rapidly mobilize and initiate hair regeneration. In contrast, HF-SCs are protected by high actomyosin contractility and a stiffer microenvironment, ensuring their insulation and quiescence.
Mechanistically, the researchers discovered that miR-205, a microRNA, targets many genes involved in regulating the actomyosin network, as well as Piezo1. Through genome-wide detection and analysis, they found that while each mRNA is only mildly reduced upon miR-205 induction, the collective impact on cell mechanics is substantial. Importantly, miR-205 is transcriptionally targeted by ΔNp63, a transcription factor involved in epithelial stem cell self-renewal. The downregulation of both ΔNp63 and miR-205 in aging HF-SCs correlates with reduced self-renewal ability and increased stiffness.
The study’s findings hold promising implications for hair regeneration. Induction of miR-205 promotes hair regeneration in both young and old mice by modulating cell mechanics through the reversible downregulation of many genes. This approach overrides inhibitory signaling pathways and correctly activates key signaling pathways involved in hair regeneration, such as FGF and WNT.
The reversible gene expression regulation and the potential for nanoparticle delivery of small RNA make miR-205 an intriguing candidate for stimulating adult hair regeneration by fine-tuning gene expression through transient modulation of cell mechanics.
Cell size control and mechanics play fundamental roles in cell physiology and tissue homeostasis. This study highlights the dynamic changes in cell size and subsequent cell cycle reentry as a mechanism for sensing and responding to changes in mechanical forces during homeostasis, wound repair, and aging.
