Human epithelial stem cell survival within their niche requires “tonic” cannabinoid receptor 1-signalling—Lessons from the hair follicle
Koji Sugawara
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorStephan Tiede
Department of Biochemistry, Children’s Hospital, University of Hamburg, Hamburg, Germany
Search for more papers by this authorTalveen Purba
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
Search for more papers by this authorMatthew Harries
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester, UK
Search for more papers by this authorDaisuke Tsuruta
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorCorresponding Author
Ralf Paus
Monasterium Laboratory, Münster, Germany
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
Correspondence
Ralf Paus, Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Email: [email protected]
Search for more papers by this authorKoji Sugawara
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorStephan Tiede
Department of Biochemistry, Children’s Hospital, University of Hamburg, Hamburg, Germany
Search for more papers by this authorTalveen Purba
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
Search for more papers by this authorMatthew Harries
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester, UK
Search for more papers by this authorDaisuke Tsuruta
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorCorresponding Author
Ralf Paus
Monasterium Laboratory, Münster, Germany
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
Correspondence
Ralf Paus, Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Email: [email protected]
Search for more papers by this authorAbstract
The endocannabinoid system (ECS) regulates multiple aspects of human epithelial physiology, including inhibition/stimulation of keratinocyte proliferation/apoptosis, respectively. Yet, how the ECS impacts on human adult epithelial stem cell (eSC) functions remains unknown. Scalp hair follicles (HFs) offer a clinically relevant, prototypic model system for studying this directly within the native human stem cell niche. Here, we show in organ-cultured human HFs that, unexpectedly, selective activation of cannabinoid receptor-1 (CB1)-mediated signalling via the MAPK (MEK/Erk 1/2) and Akt pathways significantly increases the number and proliferation of cytokeratin CK15+ or CK19+ human HF bulge eSCs in situ, and enhances CK15 promoter activity in situ. In striking contrast, CB1-stimulation promotes apoptosis in the differentiated progeny of these eSCs (CK6+ HF keratinocytes). Instead, intrafollicular CB1 gene knockdown or CB1 antagonist treatment significantly reduces human HF eSCs numbers and stimulates their apoptosis, while CB1 knockout mice exhibit a reduced bulge eSCs pool in vivo. This identifies “tonic” CB1 signalling as a required survival stimulus for adult human HF eSCs within their niche. This novel concept must be taken into account whenever the human ECS is targeted therapeutically.
CONFLICT OF INTEREST
The authors have declared that no conflict of interest exists. However, for the record, R. P. is founder & CEO of a skin research CRO that engages in HF organ culture (www.monasteriumlab.com), while T. B. consults for this CRO and for another company engaged in ECS targeting therapeutics (Phytecs, INC., Los Angeles, CA, USA).
Open Research
DATA AVAILABILITY STATEMENT
All primary data, detailed protocols and non-commercially available materials can be requested from the corresponding author.
Supporting Information
| Filename | Description |
|---|---|
| exd14294-sup-0001-FigS1.tifTIFF image, 18.1 MB | Supplementary Fig S1. Controls of immunolabeling for CB1 |
| exd14294-sup-0002-FigS2.tifTIFF image, 6.7 MB | Supplementary Fig S2. CB1 stimulation induces human HF eSCs proliferation but does not induce apoptosis |
| exd14294-sup-0003-FigS3.tifTIFF image, 2.2 MB | Supplementary Fig S3. GPR55 is not involved on human HF SCs |
| exd14294-sup-0004-FigS4.tifTIFF image, 4.5 MB | Supplementary Fig S4. CB1 gene silencing in organ cultured human HFs |
| exd14294-sup-0005-FigS5.tifTIFF image, 2.8 MB | Supplementary Fig S5. CB1 upregulates the expressions of p-Erk 1/2 and p-Akt on isolated human HF bulge cells |
| exd14294-sup-0006-FigS6.tifTIFF image, 1.4 MB | Supplementary Fig S6. A schematic representation of the effects of CB1 stimulation on various types of epithelial cells within the human HF |
| exd14294-sup-0007-FigS7.tifTIFF image, 7.2 MB | Supplementary Fig S7. Down-regulation of CB1 immunoreactivity in the bulge region of HFs from patients with LPP |
| exd14294-sup-0008-Supinfo.docxWord document, 35.1 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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