In oncology, permanent chemotherapy-induced alopecia (pCIA) remains an unfulfilled clinical
need. 
Irreversible hair loss may result from permanent damage of hair follicle bulge epithelial stem cells (HFeSCs),
some of which may undergo epithelial-mesenchymal transition (EMT). To prove our hypothesis, we treated ex
vivo full-length HFs with 4HC, a cyclophosphamide metabolite 4HC, which routinely induces reversible CIA and
sometimes pCIA. 
PPARγ signaling is known to have a protective role in eSCs biology. Therefore, we additionally tested whether
NAC-GED-0507-Levo (NACGED), a PPARγ modulator, may protect HFs from 4HC-induced damage. Ex vivo,
treatment with 4HC (3µM, 30µM) induced HF cytotoxicity and promoted dystrophic catagen development.
Moreover, 4HC caused reduction of CK15+ bulge cells number, mainly by inducing apoptosis. Interestingly,
4HC also induced EMT in the bulge epithelium, as indicated by decreased E-cadherin expression, upregulation
of fibronectin and appearance of vimentin+ intra-bulge cells. HFs pretreatment with 0.01-1mM NACGED before
addition of 4HC provided relative protection from induction of cytotoxicity without preventing catagen
development. 
Finally, NACGED treatment also antagonized CIA-induced intra-bulge EMT by counteracting both E-cadherin
expression reduction and increased vimentin+ cells number. Our data suggest that pCIA irreversibility may
indeed result from apoptosis and/or EMT-mediated destruction of CK15+bulge eSCs. Modulation of PPARγ
signaling could provide an effective strategy for managing permanent hair loss in chemotherapy-treated cancer

PPARg signaling modulation protects from hair follicle bulge stem cell damage and cyclophosphamide-induced hair follicle cytotoxicity