Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis

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Abstract

The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells1. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1–15 (Krt1-15) promoter2. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted3,4. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.

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Figure 1: Administration of ganciclovir to Krt1-15–HSV-TK mice injures hair follicle bulge cells.
Figure 2: Hair follicles in grafted Krt1-15–HSV-TK ROSA26 skin are destroyed, but epidermis survives, after administration of ganciclovir.
Figure 3: Bulge cells do not contribute to epidermal renewal under normal conditions.
Figure 4: Lineage analysis of bulge cells after wounding.

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Acknowledgements

We thank J. Richa for generating transgenic mice and L. Ash for preparation of histological sections. This work was supported by US National Institutes of Health grants AR46837 (to G.C.) and CA97957 (to R.J.M. and G.C.).

Author information

Correspondence to George Cotsarelis.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Incisional wounding results. (PDF 246 kb)

Supplementary Fig. 2

Tape stripping results. (PDF 361 kb)

Supplementary Fig. 3

Bulge-derived cells transiently repopulate reepithelialized epidermis. (PDF 541 kb)

Supplementary Fig. 4

Epidermal markers in bulge-derived cells. (PDF 79 kb)

Supplementary Table

Percentage of lacZ-positive cells remains constant over time. (PDF 15 kb)

Supplementary Note (PDF 42 kb)

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Ito, M., Liu, Y., Yang, Z. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11, 1351–1354 (2005) doi:10.1038/nm1328

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