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Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors.

ABSTRACT: How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Using Tbx18(Cre) to target embryonic DP precursors, we ablate the transcription factor Sox2 early and efficiently, resulting in diminished hair shaft outgrowth. We find that DP niche expression of Sox2 controls the migration speed of differentiating hair shaft progenitors. Transcriptional profiling of Sox2 null DPs reveals increased Bmp6 and decreased BMP inhibitor Sostdc1, a direct Sox2 transcriptional target. Subsequently, we identify upregulated BMP signaling in knockout hair shaft progenitors and demonstrate that Bmp6 inhibits cell migration, an effect that can be attenuated by Sostdc1. A shorter and Sox2-negative hair type lacks Sostdc1 in the DP and shows reduced migration and increased BMP activity of hair shaft progenitors. Collectively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk.

SUBMITTER: Clavel C

PROVIDER: S-EPMC3500526 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors.

Clavel Carlos C Grisanti Laura L Zemla Roland R Rezza Amelie A Barros Rita R Sennett Rachel R Mazloom Amin Reza AR Chung Chi-Yeh CY Cai Xiaoqiang X Cai Chen-Leng CL Pevny Larysa L Nicolis Silvia S Ma'ayan Avi A Rendl Michael M

Developmental cell 20121101 5

How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Using Tbx18(Cre) to target embryonic DP precursors, we ablate the transcription factor Sox2 early and efficiently, resulting in diminished hair shaft outgrowth. We find that DP niche expression of Sox2 controls the migration speed of differentiating hair shaft progenitors. Transcriptional profiling of Sox2 null DPs reveals increased Bmp6 and decreased BMP inhibitor Sostdc1, a direct Sox ...[more]

PMID: 23153495

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Project description:BackgroundHair loss is a prevalent medical problem in both men and women. Maintaining the potential hair inductivity of dermal papilla cells (DPCs) during cell culture is the main factor in hair follicle morphogenesis and regeneration. The present study was conducted to compare the effects of different concentrations of human hair outer root sheath cell (HHORSC) and platelet lysis (PL) exosomes to maintain hair inductivity of the human dermal papilla cells (hDPCs).MethodsIn this study, hDPCs and HHORSCs were isolated from healthy hair samples. Specific markers of hDPCs (versican, α-SMA) and HHORSCs (K15) were evaluated using flow cytometric and immunocytochemical techniques. The exosomes were isolated from HHORSCs and PL with ultracentrifugation technique. Western blot was used to detect specific markers of HHORSCs and PL exosomes. Particle size and distribution of the exosomes were analyzed by NanoSight dynamic light NanoSight Dynamic Light Scattering. Different methods such as proliferation test (MTS assay), migration test (Transwell assay) were used to evaluate the effects of different concentrations of exosomes (2,550,100 µg/ml) derived from HHORSC and PL on hDPCs. Expression of specific genes in the hair follicle inductivity, including ALP, versican and α-SMA were also evaluated using real time-PCR.ResultsThe flow cytometry of the specific cytoplasmic markers of the hDPCs and HHORSCs showed expression of versican (77%), α-SMA (55.2%) and K15 (73.2%). The result of particle size and distribution of the exosomes were analyzed by NanoSight dynamic light NanoSight Dynamic Light Scattering, which revealed the majority of HHORSC and PL exosomes were 30-150 nm. For 100 µg/ml of HHORSC exosomes, the expressions of ALP, versican and α-SMA proteins respectively increased by a factor of 2.1, 1.7and 1.3 compared to those in the control group.ConclusionIn summary, we applied HHORSC exosomes as a new method to support hair inductivity of dermal papilla cells and improve the outcome for the treatment of hair loss.

Project description:In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge are regulated by the surrounding microenvironment, or niche. The activation of such stem cells is cyclic, involving periodic beta-catenin activity. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/beta-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.

Dataset Information

Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors.

Publications

Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors.

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