A novel and safe small molecule enhances hair follicle regeneration by facilitating metabolic reprogramming

Abstract

Targeting hair follicle regeneration has been investigated for the treatment of hair loss, and fundamental studies investigating stem cells and their niche have been described. However, knowledge of stem cell metabolism and the specific regulation of bioenergetics during the hair regeneration process is currently insufficient. Here, we report the hair regrowth-promoting effect of a newly synthesized novel small molecule, IM176OUT05 (IM), which activates stem cell metabolism. IM facilitated stemness induction and maintenance during an induced pluripotent stem cell generation process. IM treatment mildly inhibited mitochondrial oxidative phosphorylation and concurrently increased glycolysis, which accelerated stemness induction during the early phase of reprogramming. More importantly, the topical application of IM accelerated hair follicle regeneration by stimulating the progression of the hair follicle cycle to the anagen phase and increased the hair follicle number in mice. Furthermore, the stem cell population with a glycolytic metabotype appeared slightly earlier in the IM-treated mice. Stem cell and niche signaling involved in the hair regeneration process was also activated by the IM treatment during the early phase of hair follicle regeneration. Overall, these results show that the novel small molecule IM promotes tissue regeneration, specifically in hair regrowth, by restructuring the metabolic configuration of stem cells.

Small Molecule Treatments Improve Differentiation Potential of Human Amniotic Fluid Stem Cells

“…Also, both oxidative phosphorylation ( NRF1 , HIF1 α, PPARGC1A ) and glycolytic ( ERR α, PKM , PDK1 , LDHA ) genes are upregulated after 96 h treatments. Small molecules are known to improve stem cell function by regulation of cellular metabolism ( Son et al, 2018 ). And several studies suggest that the initiation phase of cell reprogramming could be characterized by a phenomenon called transient hyper-energetic metabolism, which is a hybrid of high OxPhos and high glycolysis.…”

Restoring aged stem cell functionality: Current progress and future directions

“…Both Drosophila ISCs and murine HFSCs showed mitigated age‐associated effects (reduction of DNA damage, hyperproliferation, and centrosome amplification of aged ISCs) 152,153 and overall improved function of HFSCs 154 after metformin or IM176OUT05, a molecule derived from metformin, treatment. However, in mouse MuSCs, 21 days of metformin treatment led to undesirable responses including delayed activation, slowed muscle regeneration, and reduced MuSC size 155 …”

Bioactive Molecules for Skin Repair and Regeneration: Progress and Perspectives

“…And the latest study produced EpSCs from iPSCs using the same method as mentioned above with minor modifications; iPSC-derived EpSCs seeding on the human acellular amniotic membrane (hAAM) promoted the construction of hair follicles and interfollicular epidermis and restored skin functions after transplantation [84]. IM176OUT05 activated HFSC metabolism and further promoted the expansion of ki67-positive progenitors during the early phases of hair follicle regeneration so that IM176OUT05 could be a candidate drug to improve tissue regeneration with high solubility, greater potency, and bioavailability [85].…”