RESUMO
Runx1 controls hematopoietic stem cell emergence and hair follicle stem cell (HFSC) activation and proliferation in adult skin. Here we use lineage tracing and mouse genetic manipulation to address the role of Runx1 in the embryonic development of HFSCs. We find Runx1 is expressed in distinct classes of embryonic skin precursors for short-term HF progenitors, adult HFSCs, and mesenchymal progenitors. Runx1 acts in the embryonic epithelium for timely emergence of adult HFSCs and short-term progenitors, but is dispensable for both of them. In contrast, Runx1 is strictly needed in the embryonic mesenchyme for proper adult HFSC differentiation and long-term skin integrity. Our data implicate Runx1 in epithelial cell adhesion and migration and in regulation of paracrine epithelial-mesenchymal cross talk. The latter involves Lef1 and Wnt signaling modulation in opposing directions from two distinct skin compartments. Thus, a master regulator of hematopoiesis also controls HFSC emergence and maintenance via modulation of bidirectional cross talking between nascent stem cells and their niche.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Folículo Piloso/citologia , Pele/metabolismo , Células-Tronco/metabolismo , Animais , Adesão Celular , Movimento Celular , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Folículo Piloso/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Pele/embriologia , Proteínas Wnt/metabolismoRESUMO
Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.
Assuntos
Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Folículo Piloso/citologia , Neoplasias Epiteliais e Glandulares/metabolismo , Pele/patologia , Células-Tronco/fisiologia , Animais , Biomarcadores/metabolismo , Ciclo Celular/fisiologia , Linhagem da Célula , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Folículo Piloso/fisiologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Epiteliais e Glandulares/patologia , Fenótipo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Pele/citologia , Pele/metabolismo , Células-Tronco/citologiaRESUMO
Aml1/Runx1 controls developmental aspects of several tissues, is a master regulator of blood stem cells, and plays a role in leukemia. However, it is unclear whether it functions in tissue stem cells other than blood. Here, we have investigated the role of Runx1 in mouse hair follicle stem cells by conditional ablation in epithelial cells. Runx1 disruption affects hair follicle stem cell activation, but not their maintenance, proliferation or differentiation potential. Adult mutant mice exhibit impaired de novo production of hair shafts and all temporary hair cell lineages, owing to a prolonged quiescent phase of the first hair cycle. The lag of stem cell activity is reversed by skin injury. Our work suggests a degree of functional overlap in Runx1 regulation of blood and hair follicle stem cells at an equivalent time point in the development of these two tissues.