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Psoriasis is a common inflammatory skin disease involving a cross-talk between epidermal and immune cells. The role of specific epidermal stem cell populations, including hair follicle stem cells (HF-SCs) in psoriasis is not well defined. Here, we show reduced expression of c-JUN and JUNB in bulge HF-SCs in patients with scalp psoriasis. Using lineage tracing in mouse models of skin inflammation with inducible deletion of c-Jun and JunB, we found that mutant bulge HF-SCs initiate epidermal hyperplasia and skin inflammation. Mechanistically, thymic stromal lymphopoietin (TSLP) was identified in mutant cells as a paracrine factor stimulating proliferation of neighboring non-mutant epidermal cells, while mutant inter-follicular epidermal (IFE) cells are lost over time. Blocking TSLP in psoriasis-like mice reduced skin inflammation and decreased epidermal proliferation, VEGFα expression, and STAT5 activation. These findings unravel distinct roles of HF-SCs and IFE cells in inflammatory skin disease and provide novel mechanistic insights into epidermal cell interactions in inflammation. ; We thank Drs. M. Serrano and M. Perez-Moreno for the Gt(ROSA)26Sortrn4(ACTB-tdTomato,-EGFP)Luo/J and K15-Cre-PGR mouse lines. We are very grateful to Drs. M. Perez-Moreno, F. Real, O. Uluckan, L. Bakiri and the laboratory members of the Sibilia and Wagner groups for critical reading of the manuscript and valuable suggestions. We thank V. Bermeo, G. Medrano, S. Leceta, O. Grana, and M. Perez for their technical help and IT support. We acknowledge R. Paus laboratory members for the shipment of hair follicle samples. N.G.L. received funding from the People programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 608765. A.I is funded by the Institute of Health Carlos III (PI16/01430). The Wagner laboratory was funded by a grant from the Spanish Ministry of Economy and competitiveness (SAF2015-70857RE, cofounded by the European Regional Development Fund) and is ...

et al. ; The dermal Panniculus carnosus (PC) muscle is important for wound contraction in lower mammals and represents an interesting model of muscle regeneration due to its high cell turnover. The resident satellite cells (the bona fide muscle stem cells) remain poorly characterized. Here we analyzed PC satellite cells with regard to developmental origin and purported function. Lineage tracing shows that they originate in Myf5, Pax3/Pax7 cell populations. Skin and muscle wounding increased PC myofiber turnover, with the satellite cell progeny being involved in muscle regeneration but with no detectable contribution to the wound-bed myofibroblasts. Since hematopoietic stem cells fuse to PC myofibers in the absence of injury, we also studied the contribution of bone marrow-derived cells to the PC satellite cell compartment, demonstrating that cells of donor origin are capable of repopulating the PC muscle stem cell niche after irradiation and bone marrow transplantation but may not fully acquire the relevant myogenic commitment. ; This work was supported by grants from Instituto de Salud Carlos III (ISCIII; PS09/00660, PI13/02172, and PI14/7436), Gobierno Vasco (SAIO12-PE12BN008) from Spain and the European Union (POCTEFA-INTERREG IV A program; REFBIO13/BIOD/006 and REFBIO13/BIOD/009). N.N.G. received a studentship from the Department of Education, University and Research of the Basque Government (PRE2013-1-1168). P.G.P. received fellowships from the Department of Health of the Basque government (2013011016), EMBO (Short-Term; ASTF 542–2013), and Boehringer Ingelheim Fonds. M.L.M. and J.J.C. were supported by a Marie Curie Career Integration Grant from the European Commission (PEOPLE-CIG/1590). A.I. was supported by the Programa I3SNS (CES09/015) from ISCIII and by Osakidetza-Servicio Vasco de Salud (Spain). ; Peer Reviewed

Human myogenic precursor cells have been isolated and expanded from a number of skeletal muscles, but alternative donor biopsy sites must be sought after in diseases where muscle damage is widespread. Biopsy sites must be relatively accessible, and the biopsied muscle dispensable. Here, we aimed to histologically characterize the cremaster muscle with regard number of satellite cells and regenerative fibres, and to isolate and characterize human cremaster muscle-derived stem/precursor cells in adult male donors with the objective of characterizing this muscle as a novel source of myogenic precursor cells. Cremaster muscle biopsies (or adjacent non-muscle tissue for negative controls; N = 19) were taken from male patients undergoing routine surgery for urogenital pathology. Myosphere cultures were derived and tested for their in vitro and in vivo myogenic differentiation and muscle regeneration capacities. Cremaster-derived myogenic precursor cells were maintained by myosphere culture and efficiently differentiated to myotubes in adhesion culture. Upon transplantation to an immunocompromised mouse model of cardiotoxin-induced acute muscle damage, human cremaster-derived myogenic precursor cells survived to the transplants and contributed to muscle regeneration. These precursors are a good candidate for cell therapy approaches of skeletal muscle. Due to their location and developmental origin, we propose that they might be best suited for regeneration of the rhabdosphincter in patients undergoing stress urinary incontinence after radical prostatectomy. ; We thank patients and medical personnel for their generous involvement in the study. We also acknowledge the help of Biodonostia Animal and Experimental Operations Facility. This work was supported by grants from Ministerio de Economía y Competitividad (RTC-2015-3750-1) and Instituto de Salud Carlos III (PI13/02172, PI16/01430) to A.I., co-funded by the European Union (ERDF/ESF, 'Investing in your future'). N.N.-G. received a studentship from the Department of ...

Transcriptomic data of dermal cell fractions are deposited in NCBI's Gene Expression Omnibus (Edgar et al., 2002) under accession number GEO: GSE67693. ; The dermal Panniculus carnosus (PC) muscle is important for wound contraction in lower mammals and represents an interesting model of muscle regeneration due to its high cell turnover. The resident satellite cells (the bona fide muscle stem cells) remain poorly characterized. Here we analyzed PC satellite cells with regard to developmental origin and purported function. Lineage tracing shows that they originate in Myf5(+), Pax3/Pax7(+) cell populations. Skin and muscle wounding increased PC myofiber turnover, with the satellite cell progeny being involved in muscle regeneration but with no detectable contribution to the wound-bed myofibroblasts. Since hematopoietic stem cells fuse to PC myofibers in the absence of injury, we also studied the contribution of bone marrow-derived cells to the PC satellite cell compartment, demonstrating that cells of donor origin are capable of repopulating the PC muscle stem cell niche after irradiation and bone marrow transplantation but may not fully acquire the relevant myogenic commitment. ; We thank investigators for monoclonal antibodies A4.1025 (H.M. Blau) and F5D (W.E. Wright), which were obtained from the Developmental Studies Hybridoma Bank (developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA). Special thanks to G. Cossu for critical reading of the manuscript. We are also grateful to F. Costantini, C.-M. Fan, C. Lepper, M.J. Sánchez-Sanz, H. Sakai, and S. Tajbakhsh for kindly providing study materials; S. Lamarre of the GeT-Biochip facility for help in the microarray data; D. Ortiz de Urbina, J.C. Mazabuel, and A. Guisasola for help with irradiation protocol; and A. Aduriz, A. Pavón, and M. P. López-Mato for help with FACS analyses. This work was supported by grants from Instituto de Salud Carlos III (ISCIII; PS09/00660, PI13/02172, and PI14/7436), Gobierno Vasco (SAIO12-PE12BN008) from Spain and the European Union (POCTEFA-INTERREG IV A program; REFBIO13/BIOD/006 and REFBIO13/BIOD/009). N.N.G. received a studentship from the Department of Education, University and Research of the Basque Government (PRE2013-1-1168). P.G.P. received fellowships from the Department of Health of the Basque government (2013011016), EMBO (Short-Term; ASTF 542–2013), and Boehringer Ingelheim Fonds. M.L.M. and J.J.C. were supported by a Marie Curie Career Integration Grant from the European Commission (PEOPLE-CIG/1590). A.I. was supported by the Programa I3SNS (CES09/015) from ISCIII and by Osakidetza-Servicio Vasco de Salud (Spain). M.G. and S.A.M. contributed equally to this work. ; Peer-reviewed ; Publisher Version