Peroxisome proliferator‐activated receptors (PPARs) are abundantly expressed in human skin, with PPAR‐γ being the most intensively investigated isoform. In various ex vivo and in vivo models, PPAR‐γ‐mediated signalling has recently surfaced as an essential element of hair follicle (HF) development, growth and stem cell biology. Moreover, the availability of novel, topically applicable PPAR‐γ modulators with a favourable toxicological profile has extended the range of potential applications in clinical dermatology. In this review, we synthesize where this field currently stands and sketch promising future research avenues, focussing on the role of PPAR‐γ‐mediated signalling in the biology and pathology of human scalp HFs, with special emphasis on scarring alopecias such as lichen planopilaris and frontal fibrosing alopecia as model human epithelial stem cell diseases. In particular, we discuss whether and how pharmacological modulation of PPAR‐γ signalling may be employed for the management of hair growth disorders, for example, in scarring alopecia (by reducing HF inflammation as well as by promoting the survival and suppressing pathological epithelial‐mesenchymal transition of keratin 15 + epithelial stem cells in the bulge) and in hirsutism/hypertrichosis (by promoting catagen development). Moreover, we explore the potential role of PPAR‐γ in androgenetic alopecia, HF energy metabolism and HF ageing, and consider clinical perspectives that emanate from the limited data available on this so far. As this field of translational human hair research is still in its infancy, many open questions exist, for which we briefly delineate selected experimental approaches that promise to generate instructive answers in the near future.
Cartilage oligomeric matrix protein (COMP) negatively influences keratinocyte proliferation via a5b1-integrin: Potential relevance of altered
Genome editing represents a promising strategy to correct COL7A1 gene mutations that cause recessive dystrophic epidermolysis bullosa (RDEB). Previously, we used programmable nucleases that create double-stranded DNA breaks (DSBs) to repair COL7A1 mutations through homology-directed repair (HDR) with an exogenous repair template. Delivery of this template can be cytotoxic and DSBs induce undesired insertions and deletions (indels) that compete with desired HDR. To overcome these limitations, we used base editors (BE), a CRISPR/Cas9-based system that uses naturally occurring or laboratory-evolved deaminating enzymes to directly convert A>G, C>T, T>C, or G>A. BE does not lead to significant DSBs, obviates the need for a repair template, and typically offers higher editing efficiencies for point mutations than HDR. We used an optimized A>G base editor (ABEmax) for the RDEB causative R185X and R525X nonsense mutations in the COL7A1gene. We delivered ABEmax mRNA with minimal toxicity into primary fibroblasts from two patients with RDEB, and observed mutation correction rates of up to 50% along with concomitant restoration of COL7A1 protein production. Indel occurrence was minimal, with an observed frequency of w2%, consistent with previous studies. Twenty predicted off-target loci were analyzed by high-throughput sequencing. Treatment with the R185X reagent showed no off-target effects, while the R525X candidate showed A>G editing at one exonic off-target site at a frequency of w6% with <0.5% indels. Base-edited human fibroblasts were injected into an immune-deficient mouse model of RDEB, and human COL7A1expressing cells were observed in vivo. 3D bioprinting was used to deposit base-edited fibroblasts in a biopolymer complex that allowed for significant fibroblast expansion in support of a scalable, ex vivo approach for skin graft generation. These findings suggest that an optimized base editing approach may provide an efficient and precise genome editing method for individualized autologous cell therapy for RDEB.
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