Hair follicle induction by cultured human hair follicle dermal stem cells

Lead Research Organisation: Durham University
Department Name: Biological and Biomedical Sciences

Abstract

Hair follicles are remarkable mini-organs that are made from skin but that contain unique stem cell populations. Using animal models we have previously demonstrated that we can remove a small group of cells, called dermal papilla cells, from the base of the adult hair follicle and multiply them in the laboratory. When we put these cells back into the skin they interact with the overlying skin epidermal cells and direct them to become completely new hair follicles. Up to now, however, other researchers have not been able to do the same thing with human dermal papilla cells. We have recently identified two things that change when the human dermal papilla cells are grown outside the body. It appears that they rapidly lose much of the signalling information that allows them to influence other cells, and they also become less sticky so that, when they go back into skin, instead of staying together and making a hair, the move off. This project will address these problems in two ways. We will use modern gene manipulation technology to restore the missing signalling molecules to the cells. We will also use grow the cells in the laboratory inside different materials and manipulate their environment such that their stickiness is restored and they remain together when returned to the skin. If successful this bioengineering of hair follicles will lead to so called ?hair cloning? and be a major advance for the treatment of different forms of baldness. It would also be a key step towards the aim of creating an engineered skin incorporating skin appendages for use in skin grafting after burns or other skin loss.

Technical Summary

To a considerable extent, our laboratory has pioneered the concept of hair follicle neogenesis using hair follicle dermal cells as the inductive source. This project provides a key enabling technological step that advances the concept of hair follicle induction towards translational use in humans. The hair follicle dermal papilla is a unique component of the hair follicle, which has been shown to be fundamental for hair follicle cycling, and when isolated from the hair follicle is capable of inducing de novo hair follicle formation (neogenesis). Nevertheless, when human dermal papilla cells are propagated in culture, the hair inductive capability of these cells is lost. By carrying out molecular profiling of dermal papilla cells after they are isolated from the hair follicle and at stages during their subsequent culture, we have established a molecular signature of these cells in relation to their inductive status. We have also demonstrated that manipulating the cultured cells to create three-dimensional structures partially restores their original molecular profile. Our hypothesis is that restoration of genes that are essential for hair follicle induction through a combination of methods will fully restore the ability of dermal papilla cells to induce de novo hair follicles. 1) From our profiling we will introduce key missing transcription factors by transduction ? we will also introduce dermal papilla signature reporter genes into the cells 2) We will manipulate culture conditions by adding secreted factors elucidated from epithelial cells; 3) By spatially restricting three dimensional dermal cell cultures either in a bioengineered matrix or by surrounding them with epidermal cells we will alter the interaction between cells in such a way that we promote a functional in vivo dermal papilla profile. The inductive status of the cells will be tested throughout, using different in vivo functional studies, the most stringent of which assesses follicle neogenesis directly in human skin pre-grafted to immunocompromised mice. The use of these functional assays will be governed in part by reporter readouts. A successful outcome at the end of this project will firmly establish the proof-of-principle for procedures required to achieve hair follicle induction in the clinical setting, thereby providing the opportunity for rapid translational development. Moreover, while bioengineering of hair follicles is an innovative alternative in the hair follicle transplantation field, it is also a key step towards the ultimate aim of creating an engineered skin incorporating skin appendages for skin grafting and replacement.

Publications

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Driskell RR (2014) Defining dermal adipose tissue. in Experimental dermatology

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Higgins CA (2017) Multifaceted role of hair follicle dermal cells in bioengineered skins. in The British journal of dermatology

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Higgins CA (2013) Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. in Proceedings of the National Academy of Sciences of the United States of America

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Higgins CA (2012) Reprogramming of human hair follicle dermal papilla cells into induced pluripotent stem cells. in The Journal of investigative dermatology

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Jahoda CAB (2016) What Lies Beneath: Wnt/ß-Catenin Signaling and Cell Fate in the Lower Dermis. in The Journal of investigative dermatology

 
Title Microarray data from cultured human hair follicle dermal papilla cells. 
Description This is a microarray database of cultured human hair follicle dermal papilla cells at different time intervals into culture and following restoration of 3 dimensional morphology. It shows the changes of gene expression that correspond to the loss of inductivity (function) by the hair follicle cells, and those associated with restoration of function in a 3 dimensional environment. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact I has allowed the identification of master regulator genes that might allow the reprogramming of other dermal cells to become specialist hair follicle dermal cells and induce the formation of new hair follicles in skin. 
 
Description Aberdam Lab 
Organisation Paris Diderot University
Country France 
Sector Academic/University 
PI Contribution We have shared technical expertise, cell lines, etc with this laboratory, and we are working on a common project.
Collaborator Contribution Up to now, they have just provided ideas.
Impact None as yet.
Start Year 2014
 
Description Angela Christiano 
Organisation Columbia University
Department Department of Genetics and Development
Country United States 
Sector Academic/University 
PI Contribution We have worked closely with this laboratory, teaching them specific experimental techniques including functional assays in skin.
Collaborator Contribution They have provided us with useful molecular data that underpins some of the ongoing stem cell biology in the current grant. Specifically they have helped in bioinformatic analysis of microarray data. They have also provided facilities and equipment for visiting researchers form our laboratory.
Impact This collaboration has had a big impact on the training and experience of the researchers involved on both sides. The notable outcomes will be in the form of future publications described in the last section "knowledge and future potential" and in ongoing knowledge transfer. The most recent outputs of this collaboration are 2 joint papers, seen in the "Publications" section.
 
Description Botchkarev Lab 
Organisation University of Bradford
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided data from our work to the Bradford group.
Collaborator Contribution The Bradford group have carried out bioinformatics analysis of our data. We are writing papers and grant applications together.
Impact Papers and grant application in preparation.
Start Year 2013
 
Description National and International Television, Radio and Newspaper interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Local and national television, ITN, Sky, Russian Television, numerous radio stations BBC etc and multiple newspaper and science magazine reports in response to our PNAS paper.
The New York Times, The New Zealand Herald
CBS News, Sowetan (South Africa)
The Chronicle Herald (Canada), The Financial Times
RIA NOVOSTI (Russia), International Business Times
Capital FM (Kenya), Seattle Times (USA),ABC News (Australia)
Jagran (India), Fox News (USA), The Province (Canada), Courier Mail (Australia), News.com.au (Australia), Aspen Times (USA), The Australian , The Tribune (India) LAist Daily (USA)
Voice of America, Businessweek, Bloomberg, SPY Ghana
Guardian Express (USA), Sydney Morning Herald, The Wall Street Journal, Daily Times (Nigeria), HNGN, Times (South Africa), Miami Herald, Top News (UAE), L'express (France)

National
The Times, The Telegraph, BBC News, Sky News, Metro, The Daily Express, Daily Mail, BT News, Huffington Post, ITV News,
The Independent, The Courier, Daily Record, The Scottish Herald, The Mirror, London Evening Standard

Regional
The Journal, Sky Tyne & Wear, The Northern Echo

Other

Medical News Today, Red Orbit, Health24



Too soon to say.
Year(s) Of Engagement Activity 2013
URL http://www.thetimes.co.uk/tto/science/article3900578.ece?CMP=OTH-gnws-standard-2013_10_21 The Teleg...