Bone marrow-derived epithelial cells and hair follicle stem cells contribute to development of chronic cutaneous neoplasms

Heuijoon Park,Kelly Johnson,Kelsey Boland,Nyssa Readio,Anupama Singh,Xiangdong Yang,Ashok Singh,Samuel Asfaha,Guangchun Jin,Sonali Lad,Carol Trempus,Timothy C Wang,Douglas Londono,Kelly S Patterson,Derek Gordon,Rebecca J Morris

doi:10.1038/s41467-018-07688-8

Abstract

We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). BMDECs clustered in the lesional epithelium, expressed cytokeratins, proliferated, and stratified. We detected cytokeratin induction in plastic-adherent bone marrow cells (BMCs) cultured in the presence of filter-separated keratinocytes (KCs) and bone morphogenetic protein 5 (BMP5). Lineage-depleted BMCs migrated towards High Mobility Group Box 1 (HMGB1) protein and epidermal KCs in ex vivo invasion assays. Naive female mice receiving BMTs from DMBA-treated donors developed benign and malignant lesions after TPA promotion alone. We conclude that BMDECs contribute to the development of papillomas and dysplasia, demonstrating a systemic contribution to these lesions. Furthermore, carcinogen-exposed BMCs can initiate benign and malignant lesions upon tumor promotion. Ultimately, these findings may suggest targets for treatment of non-melanoma skin cancers.

Highlights

We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA)
Whole bone marrow cells (BMCs) were harvested from the femurs and tibiae of male C57BL/6 mice, and plastic-adherent BMCs were co-cultured with 1-week-old primary mouse epidermal KCs separated by an impassable filter (Supplementary Figure 1a) in the presence of mouse mesenchymal stem cell (MSC) culture medium (MesenCult)
We have reported here that in vivo, recruitment, epithelialization, and proliferation of bone marrow-derived cells (BMDCs) occurred during cutaneous carcinogenesis

Summary

Introduction

We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). Carcinogen-exposed BMCs can initiate benign and malignant lesions upon tumor promotion These findings may suggest targets for treatment of non-melanoma skin cancers. Acute cutaneous wound healing following allogeneic BMT revealed that genetically labeled or Y chromosome-positive BMDCs engrafted within the epidermal germinal layer at the site of the injury, and that a subset of BMDCs directly differentiated into cytokeratin and Ki67-expressing cells without cell fusion[9,10,11]. A subpopulation of platelet-derived growth factor receptor (PDGFR)alpha-positive, non-hematopoietic BMDCs cells were found to engraft to skin following acute injury[13]. Despite these provocative observations, the number of recruited BMCs was quite small. We conclude that large numbers of BMDECs are recruited to a subset of cutaneous papillomas and dysplastic ulcers and reflect a previously unrecognized systemic contribution to these lesions

Methods

Results

Conclusion