Hair follicle renewal: authentic morphogenesis that depends on a complex progression of stem cell lineages

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Abstract
The hair follicle (HF) grows during the anagen phase from precursors in the matrix that give rise to each differentiated HF layer. Little is known about the lineal relationship between these layer-restricted precursors and HF stem cells. To understand how the HF stem cells regenerate the typical anagen organization, we conducted in vivo clonal analysis of key stages of the HF cycle in mice. Unexpectedly, we found that the pool of HF stem cells contains precursors with both multipotent and restricted contributions. This implies that the lineal relationships between HF stem cells (persisting during telogen) and layer-restricted precursors (in the germinative layer), responsible for HF elongation during anagen, are not stereotyped. Formation of the matrix at each cycle is accompanied by the transient expansion of an intermediary pool of precursors at the origin of the germinative layer and by the progressive restriction of cell dispersion. The regionalization of clonal patterns within the outer HF structure (the outer root sheath) suggests that the position of the precursors might be a crucial factor in determining their fate. The presence of HF stem cells with multipotent contribution and the progressive segregation of HF lineages upon anagen activation indicate that each HF renewal cycle constitutes an authentic morphogenetic process. A comprehensive model was constructed based on the different clonal patterns observed. In this model, the positions of the precursors relative to the dermal papilla together with the progressive restriction of cell dispersion are part of the mechanism that restricts their contribution to the different HF lineages.