Compositions and methods for promoting hair growth with mpc1 inhibitors
A technology of hair growth and composition, applied in the field of composition and method for promoting hair growth using MPC1 inhibitors, capable of solving problems such as birth defects in pregnant women
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Embodiment 1
[0195] Example 1: Enrichment of lactate dehydrogenase activity in the hair follicle stem cell niche
[0196] Numerous studies have revealed a unique gene expression imprint of HFSC on other follicular cells or interfollicular epidermal cells 3-6 . Many of these imprints are regulated by transcription factors that were later shown to play important roles in HFSC homeostasis 7 . Lactate dehydrogenase in mammals is most commonly encoded by the Ldha and Ldhb genes, the protein products of which form homo- or hetero-tetramers to catalyze the reduction of pyruvate to lactate and the conversion of lactate to NAD in an NADH-dependent manner. + Oxidation to pyruvate in a dependent manner 9 . By immunostaining, in situ quiescent HFSC (resting phase) was confirmed to enrich Ldha( Figure 1a ), IHC with antibodies recognizing Ldha and Ldhb showed that only Ldha localized to the HFSC niche ( Figure 4a ).
[0197] HFSC are known to undergo successive rounds of quiescence (telogen) ...
Embodiment 2
[0202] Example 2: Loss of Ldh activity blocks HFSC activation
[0203] To determine whether Ldh activity is functionally related to the ability of HFSCs to remain quiescent or to activate at the onset of the hair cycle, Ldha was specifically deleted in HFSCs. Mice utilizing the conditional deletion of the Ldha allele 12 , this enzyme was deleted in HFSCs by crossing with mice carrying the K15CrePR allele 5 , which is known to be specifically induced by mifepristone in HFSC. Deletion of Ldha in HFSC was induced by administration of mifepristone during the resting phase (day 50) and resulted in mosaic recombination of the conditional deletion allele that normally occurs throughout the posterior epidermis. Mice with HFSC-specific deletion of Ldha were unable to undergo a normal hair cycle, and at least 33 pairs of littermates had most hair follicles in the telogen phase at 3–4 weeks after mifepristone treatment ( Figure 2a ).
[0204] Histology revealed that WT hair follic...
Embodiment 3
[0208] Example 3: Deletion of Mpc1 in hair follicle stem cells activates a new hair cycle
[0209] K15CrePR animals were crossed with those conditionally deleted for the mitochondrial pyruvate carrier 1 (Mpc1) (K15CrePR; Mpc1 fl / fl ). Mpc1 heterodimerizes with Mpc2 to form the mitochondrial pyruvate carrier MPC, which is a transporter on the inner mitochondrial membrane required for pyruvate entry into mitochondria 15 . Loss of Mpc1 function has been shown to drive lactate production by enhancing the conversion of pyruvate to lactate through Ldh 16 .
[0210] In animals lacking Mpc1 in HFSC, a marked acceleration of the ventral and dorsal hair cycle was observed, with all the typical features of the telogen-anagen transition ( Figure 3a ) (12 pairs of littermates; for other animals, see Figure 6a ). Mifepristone-only K15CrePR by day 70; Mpc1 fl / fl Animals showed any signs of dorsal anagen. Western blotting of sorted HFSCs verified the loss of Mpc1 protein ( Figur...
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