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. 2022 Sep 28;25(10):105238.
doi: 10.1016/j.isci.2022.105238. eCollection 2022 Oct 21.

Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress

Per Fessé  1   2 , Jan Nyman  3 , Ingegerd Hermansson  3 , Maj-Lis Book  2 , Johan Ahlgren  4 , Ingela Turesson  2
Affiliations

Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress

Per Fessé et al. iScience. .

Abstract

DNA-damage response of cutaneous interfollicular melanocytes to fractionated radiotherapy was investigated by immunostaining of tissue sections from punch biopsies collected before, during, and after the treatment of patients for breast cancer. Our clinical assay with sterilized hair follicles, excluded the migration of immature melanocytes from the bulge, and highlighted interfollicular melanocytes as an autonomous self-renewing population. About thirty percent are immature. Surrounding keratinocytes induced and maintained melanocyte differentiation as long as treatment was ongoing. Concomitant with differentiation, melanocytes were protected from apoptosis by transient upregulation of Bcl-2 and CXCR2. CXCR2 upregulation also indicated the instigation of premature senescence, preventing proliferation. The stem cell factor BMI1 was constitutively expressed exclusively in interfollicular melanocytes and further upregulated upon irradiation. BMI1 prevents apoptosis, terminal differentiation, and premature senescence, allowing dedifferentiation post-treatment, by suppressing the p53/p21-and p16-mediated response and upregulating CXCR2 to genotoxic damage. The pre-treatment immature subset of interfollicular melanocytes was restored after the exposure ended.

Keywords: Cancer; Cell biology; Developmental biology; Stem cells research.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
The number of melanocytes is undisturbed following the radiotherapy course Mean number of ΔNp63-negative (formula image) cells per millimeter in the basal layer of epidermis (n = 15 patients). Error bars represent SEM. The dashed line represents the average of the data points.
Figure 2
Figure 2
A subpopulation of immature melanocytes exists in the interfollicular epidermis that differentiates temporarily during radiation exposure Mean number of cells per millimeter in the basal layer (n = 15 patients). (A) MITF-positive melanocytes (formula image) and Bcl-2-positive melanocytes (formula image). (B) MITF-negative cells (formula image) and Bcl-2-negative cells (formula image) are morphologically characterized as melanocytes. Error bars represent SEM.
Figure 3
Figure 3
Interfollicular melanocytes express BMI1 Mean number of stained cells per millimeter in the basal layer for 15 patients. (A) BMI1-positive cells (formula image) and (B) BMI1-negative cells morphologically characterized as melanocytes (formula image). Error bars represent SEM. The dashed line represents the average of the data points.
Figure 4
Figure 4
CXCR2 upregulation in melanocytes upon radiation exposure Upregulation of the cell membrane receptor CXCR2 for two patients receiving: (A) 5 × 2 Gy/week for 5 weeks and (B) 2 × 4 Gy/week for 5 weeks. CXCR2-positive melanocytes. (formula image) and CXCR2-negative cells (formula image) were morphologically characterized as melanocytes, and the total number of stained and unstained melanocytes is indicated (formula image). Reference line represents the mean number of melanocytes counted in eosin-PAS staining (Turesson et al., 2020).
Figure 5
Figure 5
The number of interfollicular melanocytes expressing pRb in individual patients Number of stained cells per millimeter in the basal layer for 15 patients expressing pRb-positive cells (formula image).
Figure 6
Figure 6
Flow chart of possible molecular pathways regulating epidermal melanocyte survival in situ upon genotoxic exposure M: melanocyte K: keratinocyte
Figure 7
Figure 7
Flow chart of possible molecular pathways regulating p53-p21 expression in interfollicular melanocytes in situ upon genotoxic exposure M: melanocyte K: keratinocyte
See this image and copyright information in PMC

References

    1. Acosta J.C., O'Loghlen A., Banito A., Guijarro M.V., Augert A., Raguz S., Fumagalli M., Da Costa M., Brown C., Popov N., et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133:1006–1018. - PubMed
    1. Barlow J.O., Maize J., Sr., Lang P.G. The density and distribution of melanocytes adjacent to melanoma and nonmelanoma skin cancers. Dermatol. Surg. 2007;33:199–207. - PubMed
    1. Basu D., Salgado C.M., Patel J.R., Zabec J., Hoehl R.M., Bauer B., Reyes-Múgica M. Pluripotency markers are differentially induced by IGF1 and bFGF in cells from patients' lesions of large/giant congenital melanocytic nevi. Biomark. Res. 2019;7:2. - PMC - PubMed
    1. Bellei B., Pitisci A., Catricalà C., Larue L., Picardo M. Wnt/beta-catenin signaling is stimulated by alpha-melanocyte-stimulating hormone in melanoma and melanocyte cells: implication in cell differentiation. Pigment Cell Melanoma Res. 2011;24:309–325. - PubMed
    1. Bertrand J.U., Steingrimsson E., Jouenne F., Bressac-de Paillerets B., Larue L. Melanoma risk and melanocyte biology. Acta Derm. Venereol. 2020;100:adv00139. - PMC - PubMed