Optogenetically Controlled TrkA Activity Improves the Regenerative Capacity of Hair‐Follicle‐Derived Stem Cells to Differentiate into Neurons and Glia

Abstract

one due to prevalent issues such as alloimmune rejection, the availability of cell sources and the potential long-term risk for tumorigenesis. [4][5][6] Hair follicles are an easily accessible structure on the skin and the stem cells harbored within them can consistently undergo self-renewal. [7,8] Hairfollicle-derived stem cells (HSCs) isolated from the bulge region of hair follicles were able to differentiate into neuronal and glial cells in vitro and also regenerate neurons in animal recipients. [8][9][10] HSCs are an ideal cell source for neural regeneration not only due to its differentiation potency to neural cell types, but also its reduced tumorigenicity as somatic stem cells, easy accessibility, as well as its lower rate for immunologic rejection during autologous transplantation.Neurotrophin signaling is a key process that determines neural stem cell function, influencing cell survival, cell division and differentiation. These effects carry on to modulate functions in fatedetermined cells, such as axonal and dendritic growth of neurons, cell death, neurotransmitter secretion, and neuronal activity. [11] Neurotrophin signaling is traditionally mediated through ligand binding to the tropomyosin receptor kinase (Trk) receptor tyrosine kinase family and, with less affinity, to the p75 neurotrophin receptor (p75 NTR ). [11][12][13] Although Trk Hair-follicle-derived stem cells (HSCs) originating from the bulge region of the mouse vibrissa hair follicle are able to differentiate into neuronal and glial lineage cells. The tropomyosin receptor kinase A (TrkA) receptor that is expressed on these cells plays key roles in mediating the survival and differentiation of neural progenitors as well as in the regulation of the growth and regeneration of different neural systems. In this study, the OptoTrkA system is introduced, which is able to stimulate TrkA activity via blue-light illumination in HSCs. This allows to determine whether TrkA signaling is capable of influencing the proliferation, migration, and neural differentiation of these somatic stem cells. It is found that OptoTrkA is able to activate downstream molecules such as ERK and AKT with blue-light illumination, and subsequently able to terminate this kinase activity in the dark. HSCs with OptoTrkA activity show an increased ability for proliferation and migration and also exhibited accelerated neuronal and glial cell differentiation. These findings suggest that the precise control of TrkA activity using optogenetic tools is a viable strategy for the regeneration of neurons from HSCs, and also provides a novel insight into the clinical application of optogenetic tools in cell-transplantation therapy.

Bioactive cell niche mediating uniform thermal stimulus for BMSC neural differentiation through TRPV1 channel activation

“…Although with advantages and flexibility due to easy operability, light stimulus is usually combined with an optogenetics tool to modulate neuro-behavior, thus restricting it to the poor tissue penetration of the visible light operator, complex processes and high process costs. 6,7 Contrary to that, thermal stimulus is relative mild and controllable, providing a more feasible and controllable tool to realize physical stimulus in neuromodulation. In many cases, thermal stimulus has been used for its anti-tumor effects by killing tumor cells with heat, and hence it is generally considered to be harmful to tissues, meaning that few studies have focused on its regulation in nerve regeneration.…”