Cell News 01/2017
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BINDER INNOVATION PRIZE 2017
the self-renewal of HFSCs during regeneration by signaling back
to the SCs to control their activation (Hsu et al., 2014b). When
a subset of HFSCs is activated at the onset of the HF growth
phase, they leave the niche to generate a new HF that grows
downward into the dermis (Muller-Rover et al., 2001).
Interestingly, when restricted by tissue architecture, the specific
SC pools within the skin epidermis remain strictly compartmen-
talized, and the pilosebaceous unit is maintained independent
of the IFE in the absence of wounding (Levy et al., 2005; Levy et
al., 2007; Nowak et al., 2008). However, upon epidermal injury
or removal from tissue and subsequent transplantation, the
specialized SCs exhibit broader potency in their new microen-
vironment. For example, transplanted HFSCs generate not only
HFs, but also IFE and sebaceous glands (Morris et al., 2004;
Oshima et al., 2001). This strongly indicates that differences
in the molecular composition of the HF and IFE niches tightly
instruct SC lineage progression, but the mechanisms remain
poorly understood.
Surprisingly, lineage tracing and ablation studies have demon-
strated that HFSCs are dispensable for HF regeneration and that
activated progeny re-populate the ablated SC compartment
to sustain hair regeneration (Hsu et al., 2011; Rompolas et al.,
2013). This indicates that the niche might be able to instruct
committed progenitors to be reprogrammed to a SC state.
Collectively these studies underscore the need to understand the
complexity of the signaling circuitry governing HFSC identity
and behavior.
Mechanisms and functions of stem cell-niche
interactions in stem cell fate decisions and
reprogramming
Intestinal SC organoid cultures that recapitulate the prolifera-
tive capacity and multipotency of their
in vivo
counterparts have
been extremely successful in elucidating mechanistic details on
intestinal SC biology (Sato and Clevers, 2013). In contrast, the
lack of a system that recapitulates the
in vivo
niche, enabling
maintenance of HFSCs in the absence of other heterologous
cell types, and allowing precise manipulation and monitoring
of HFSC fate decisions has been one of the major obstacles in
uncovering fundamental principles of HFSC regulation.
We have recently developed an
ex vivo
culture system that, for
the first time, allows to enrich and maintain HFSCs without loss
of their multipotency (Chacon-Martinez et al., 2016) (Fig.2).
We have previously deciphered how cells, through their ability
to generate force at cell-matrix adhesions, remodel their own
extracellular matrix (ECM) microenvironment (Radovanac et
al., 2013). We further demonstrated that the precise molecular
composition of the ECM within the HFSC niche is critical for
maintaining HFSC quiescence (Morgner et al., 2015). Using this
knowledge as a starting point we were able to further identify
the key molecular components of the niche: a 3-dimensional
(3D) ECM microenvironment, FGF-2, VEGF and EGF, that not
only maintain but strikingly also promote stemness
ex vivo
(Chacon-Martinez et al., 2016).
Intriguingly, studies in this system have led us to uncover that
cultured epidermal cell mixtures self-evolve into a dynamic
population equilibrium state of HFSCs and progenitors, as shown
by lineage tracing and transcriptomics analyses (Chacon-Mar-
tinez et al., 2016). This involves bidirectional signaling crosstalk
mediated by Sonic hedgehog (Shh)- and Bone morphogenetic
protein (BMP) pathways, that have been previously implicated in
regulating the crosstalk between HFSCs and their TAC progeny
(Hsu et al., 2014a), highlighting that our culture system faithful-
ly recapitulates complex signaling networks of the
in vivo
niche.
Strikingly, we observe that the bidirectional interconversion of
HFSCs and progenitor cells drives the system into equilibrium
proportions in a dynamic, self-organizing process. Moreover,
HFSCs can be derived completely
de novo
even from purified
populations of epidermal non-HFSCs (Chacon-Martinez et al.,
2016). Consequently, a stable HFSC – non-HFSC equilibrium
can evolve from a pure population of non-HFSCs (Fig.2). This
not only corroborates previous studies showing that activated
progeny re-populate an ablated SC niche and subsequently
adopt a SC fate (Hsu et al., 2014a; Rompolas et al., 2013), but
defines a set of factors that can drive this reprogramming. The
dynamic reprogramming and tunable nature of the HFSC cul-
tures together with the absence of terminal differentiation also
distinguishes our system from the classical organoid cultures
(Sato and Clevers, 2013).
Mechanical regulation of SC fate
The use of SCs in regenerative medicine is being intensively
explored due to their potential to generate or repair tissues in a
sustained manner. However, hematopoietic SCs and progenitors
that are being used in treatment of hematopoietic disorders
remain the only SC type that has reached the clinics. Although
various SCs can be isolated and studied in vitro, these cells
generally lose key functions, limiting their potential for tissue
engineering or organogenesis. This limitation had led to exten-
sive efforts to identify specific molecules and cellular compo-
nents of SC niches that would promote SC function or retain the
stemness state (Shin and Mooney, 2016). Importantly, advances
in biomaterials and in the ability to experimentally address me-
chanical aspects of biology have led to a key new paradigm in
SC biology: SCs generate forces and sense physical properties of
the matrix through adhesion, which activate signaling cascades
to control SC fate and function (Fedorchak et al., 2014; Heisen-
berg and Bellaiche, 2013). Thus, understanding the mechanisms
that sense physical forces and how they control organ growth
and patterning through SC fate and self-organization is a key
unresolved step towards generation of successful SC therapies.
