Cell News 02/2017
14
Summary
Our research aims to understand how complex but stereotyped
tissues are formed, maintained and regenerated through local
deformation, growth, differentiation and remodeling. To decipher
this fundamental question it is important to understand how
single cell behaviors are coordinated on the population level and
how population-level dynamics is coupled to tissue architecture.
Uncovering these regulatory principles will further facilitate de-
velopment of stem cell (SC) therapies and effective treatments
against cancers.
As a self-renewing organ maintained by multiple distinct SC
populations, the mammalian epidermis represents an outstand-
ing, clinically highly relevant research paradigm to address these
questions. Epidermal and hair follicle stem cells (HFSCs) fuel
tissue self-renewal, repair epidermal injuries and, when deregu-
lated, initiate carcinogenesis. We aim to decipher how these SCs
interact with their niches to regulate fate decisions and phe-
notypic plasticity. In addition, we strive to understand the role
of mechanical forces in the regulation of nuclear and genomic
architecture, and thereby in gene expression and SC fate. These
focus areas are pursued by an interdisciplinary research strategy
that builds on mouse genetics and molecular cell biology, com-
bined with state-of-the-art biological imaging, biochemistry,
biophysics and theoretical approaches.
The hair follicle stem cell niche as a paradigm for
adult stem cell studies
Adult somatic SCs fuel tissue renewal, repair, and remodeling to
maintain organ structure and function by tuning their prolif-
eration and differentiation rates to match the changing needs
of their resident tissues. Given their potency, even incremental
alterations in SC behavior could lead to substantial chang-
es in tissue size and architecture. Yet, these types of effects
are strikingly rare, strongly implying that SCs are under tight
homeostatic regulation that allows the system to react rapid-
ly to disturbances and to efficiently restore proper functions.
However, such mechanisms of population-level regulation are
poorly understood.
SCs reside in spatially distinct microenvironments termed niches
that consist of neighboring cells, extracellular matrix and signals
derived from these compartments. Niches integrate signals that
control the balanced response of SCs to the needs of organisms,
prevent SC depletion while at the same time restrict excessive
SC expansion into the surrounding tissue (Blanpain and Fuchs,
2014; Morrison and Spradling, 2008; Scadden, 2014). Although
the critical importance of niches in SC regulation has been
established, the complexity of mammalian SC niches has pre-
vented identification of the precise nature of the niche-derived
signals and hindered mechanistic studies of adult SC regulation.
The mammalian epidermis is a self-renewing organ maintained
by multiple distinct tissue-resident SC populations. Due to
its exceptional ability to combine constant self-renewal with
extreme structural robustness, the epidermis represents an
excellent, and clinically highly relevant research paradigm to
study SCs and their interactions with the niche. The mammalian
epidermis is composed of a pilosebaceous unit that consists of
the hair follicle (HF) and the sebaceous gland, with individu-
al units surrounded by the interfollicular epidermis (IFE). The
various compartments contain distinct SC populations that
facilitate the constant renewal of the IFE and HFs during post-
natal tissue homeostasis and regeneration (Blanpain and Fuchs,
2009). The bulge niche of the HF harbors quiescent hair follicle
stem cells (HFSCs) that fuel cyclical bouts of HF regeneration
and represent an outstanding paradigm for uncovering funda-
mental principles of somatic tissue-resident SC regulation and
organ self-assembly (Fig. 1). HFSCs are activated in a two-step
process: first, quiescent HFSCs are activated to generate primed
HFSCs that in a second step establish a pool of transit-amplify-
ing cells (TACs) (Greco et al., 2009; Hsu et al., 2014b). TACs are
a transition state between SCs and their differentiated progeny,
and their generation is a rate-limiting step in SC differentiation
(Fig. 1). It has recently been demonstrated that TACs coordinate
BINDER INNOVATION PRIZE 2017
Sara A. Wickström
Regulation of epidermal stem cell fate by niche-derived
signals and mechanical forces
Paul Gerson Unna Group ‘Skin Homeostasis and Ageing’,
Max Planck Institute for Biology of Ageing, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD),
University of Cologne, Germany
