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Stem cell dynamics, migration and plasticity

during wound healing
Sophie Dekoninck1 and Cédric Blanpain *
1,2

Tissue repair is critical for animal survival. The skin epidermis is particularly exposed to injuries, which necessitates rapid
repair. The coordinated action of distinct epidermal stem cells recruited from various skin regions together with other cell
types, including fibroblasts and immune cells, is required to ensure efficient and harmonious wound healing. A complex cross-
talk ensures the activation, migration and plasticity of these cells during tissue repair.

T
he skin is the first barrier protecting animals against UV radi- their heterogeneity, clonal dynamics and remarkable plasticity dur-
ation and pathogens from the external environment. It is com- ing wound healing. Finally, we discuss the role of fibroblast popula-
posed of an epithelial layer, the epidermis, and the underlying tions and immune cells during repair and regeneration.
dermis, which are separated by a basement membrane1. The epi-
dermis contains pilosebaceous units that include a hair follicle and Skin epithelial stem cells during homeostasis
sebaceous glands, and are connected with the interfollicular epi- The skin epithelium renews throughout life in a continuous turn-
dermis (IFE) through the infundibulum1. The skin epidermis also over ensured by stem and progenitor cells that balance proliferation
contains other appendages, such as sweat glands, which regulate and differentiation to replace dead and terminally differentiated
body temperature through perspiration1. The dermis is composed cells1,13,14. Epithelial stem cells reside in a specific microenvironment
of an upper (papillary) and a lower (reticular) layer of fibroblasts, called the niche that is composed of various cell types. Niche cells
blood vessels, immune cells and extracellular matrix (ECM)2,3. influence stem cell behaviour directly by cell contact or indirectly
Specialized fibroblasts form the dermal papilla, which regulates via ECM components and growth factors15. Although skin stem cells
hair follicle growth and the erector pili muscle, responsible for are able to regenerate the entire repertoire of skin epithelial lineages
pilo-erection. Partially integrated into the reticular dermis is a layer upon transplantation, lineage tracing has demonstrated that, during
of dermal adipocytes that form the dermal white adipose tissue4. physiological conditions, epidermal compartments are sustained by
Underneath the dermis, the hypodermis (or subcutaneous adipose their own pool of resident stem cells14–16 (Fig. 2a).
tissue) is composed of adipocytes, blood vessels and inflammatory During adult homeostasis, hair follicles undergo cycles of growth
cells4. This layer is important for thermoregulation and mechanical (anagen) and degeneration (catagen), followed by a resting stage
protection2,4 (Fig. 1a). (telogen)1. The hair follicle stem cells (HFSCs) responsible for cyclic
Upon tissue damage, the skin has to be repaired as quickly as regeneration are located in the permanent non-cyclic follicle portion
possible to prevent excessive blood loss and infection. Wound called the bulge17–20. HFSCs were first identified based on their slow-
healing occurs through distinct overlapping phases: haemostasis, cycling properties19,21,22. They have higher clonogenicity in vitro and
inflammation, proliferation and remodelling5. Haemostasis occurs give rise to IFE, hair follicle and sebaceous gland lineages upon trans-
immediately after tissue damage and results in the formation of a plantation17,18,20,23,24. Slow-cycling HFSCs were first isolated and char-
blood clot, which stops the haemorrhage and triggers the recruit- acterized using K5-tTA/TRE-H2BGFP and Krt15-EGFP transgenic
ment of different immune cells, including neutrophils, macrophages mice25,26, and several studies revealed the expression of bulge spe-
and lymphocytes, to prevent infection and further activate the cific markers, such as Cd34 (refs 18,23), Krt15 (refs 27,28), Krt19 (ref. 29),
inflammatory response5,6 (Fig. 1b). The proliferation phase coor- Lgr5 (ref. 30), Sox9 (refs 31,32) and Tcf3 (ref. 33). In sharp contrast to
dinates epidermal re-epithelialization and dermal repair5 (Fig. 1c). transplantation experiments, lineage tracing using Krt15-CrePR34,
The remodelling phase removes cells that are no longer neces- Shh-Cre35, Lgr5-CreER30, K19-CreER29, Sox9-Cre32 and Tcf3-CreER33
sary and induces ECM remodelling6. In small excisional wounds mouse strains established that HFSCs only contribute to hair follicle
(<​1 cm in diameter in mice), hair follicles are not reformed and regeneration during physiological conditions and do not maintain
dermal scar tissue compensates for skin loss7 (Fig. 1d). However, the sebaceous gland, infundibulum or IFE (Fig. 2a).
in large wounds (>​1 cm in diameter), regeneration of hair follicles The IFE is composed of a single layer of proliferative basal cells
(wound-induced hair follicle neogenesis (WIHN)) can be observed and several layers of differentiated non-proliferative cells1. Basal
after re-epithelialization during the remodelling phase, resembling cells replenish the suprabasal cells that are lost as terminally dif-
hair follicle embryonic development and a regeneration phase, ferentiated squames. In mice, it takes about 1 week for a basal cell to
typically 13–14 days after injury in mice7,8 (Fig. 1d). transit to the surface of the skin and about 1 month to replenish the
Although the key steps of wound healing are well described at whole IFE36. Early proliferation kinetic experiments reported main-
the tissue level, a more in-depth characterization of the behaviour of tenance of the IFE by small proliferative units that contain stem cells
individual cells at the clonal level and their fate transitions has only and progenitors37. However, lineage tracing at clonal density later
yet begun. The emergence of lineage tracing and intravital micros- demonstrated that these units do not have a fixed size or predict-
copy, coupled with transcriptional and epigenetic profiling, provide able proliferation kinetics38,39. Instead, several studies, showed that
important insights about cellular and molecular mechanisms respon- IFE homeostasis was sustained by a single population of committed
sible for wound healing9–12. In this Perspective, we describe recent progenitors that balance renewal and differentiation in a stochas-
advances with an emphasis on skin epithelial stem cell populations, tic manner38,40–43. However, further studies provided evidence that

1
Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium. 2WELBIO, Université Libre de Bruxelles, Brussels, Belgium.
*e-mail: [email protected]

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a b
Homeostasis Haemostasis and inflammation
Interfollicular epidermis

Sebaceous gland Infundibulum Hair

Arrector pili Isthmus
muscle Bulge Pilosebaceous unit
Fibrin clot
Epidermis
Papillary
dermis

Dermal Reticular Dermis

papilla dermis

Blood Dermal white

vessel adipose tissue
Subcutaneous
white adipose Hypodermis
tissue

c d
Proliferation Remodelling Large excisional wound
Wound-induced hair follicle
Small excisional wound neogenesis
Eschar Scar

Epithelial cells Papillary fibroblasts Epidermal immune cells ECM (collagen, elastin, ...)

Adipocytes Reticular fibroblasts Circulating immune cells Fibrin

Fig. 1 | Overview of skin homeostasis and wound-healing phases. a, The skin is composed of the dermis and the epidermis. In the epidermis, epithelial
cells are organized into a pilosebaceous unit (the hair follicle and its associated sebaceous glands) and the surrounding tissue (the IFE). The dermis
consists of a papillary and a reticular layer located in the upper and lower part, respectively. Dermal papilla controls the hair follicle cycle and the arrector
pili muscle ensures its movement. The dermis includes fibroblasts, blood vessels, immune cells, sensory nerves and, in its lower portion, the dermal white
adipose tissue, which contains adipocytes. Below the skin lies the hypodermis or subcutaneous white adipose tissue. b, Haemostasis and inflammation
start immediately after wounding. The fibrin clot prevents further blood loss and provides a scaffold for the migration of immune, dermal and epidermal
cells. c, During the proliferation phase, keratinocytes, fibroblasts and endothelial cells proliferate and migrate to the wound site and reform the ECM.
d, During the remodelling phase, the collagen in the dermis is remodelled and cells from earlier stages are removed. In small excisional wounds in mice,
hair follicles are not regenerated and dermal scar tissue compensates for skin loss (left panel). In large excisional injuries, WIHN can be observed after
complete re-epithelialization (right panel).

basal epidermal cells are heterogeneous and some cells, depend- Skin epithelial stem cells during wound healing
ing on the skin regions, exhibit stem cell characteristics44,45. These During wound healing, stem cells are activated and recruited
IFE stem cells (IFESCs) were more quiescent, persisted longer and from different skin regions. Interestingly, lineage restriction and
could give rise to more rapidly cycling committed progenitors with spatial confinement of resident skin stem cells are transiently lost
a shorter lifespan44,45 (Fig. 2a). Profiling of murine stem and pro- during repair, allowing contribution of multiple epidermal stem
genitor cells showed that the two populations are molecularly dif- cells15,34,54,56,57 (Fig. 2b).
ferent and that stem cells express a higher level of basal integrins, as The involvement of HFSCs in wound healing was already pro-
do human epidermal stem cells, whereas committed progenitors are posed 40 years ago after dermabrasion experiments in mice58 and
primed towards differentiation44,46. further confirmed by more-recent analyses of proliferation kinetics22.
The isthmus, a region located between the bulge and sebaceous Lineage tracing targeting labelled retaining cells26 or using Krt15-
gland, contains its own pool of resident stem cells that express Blimp1 CrePR34, Shh-Cre57, K19-CreER54 and Lgr5-CreER54 reporter strains
(ref. 47), Lgr6 (ref. 48), Lrig1 (ref. 49), Gata6 (ref. 50) or Plet1 (ref. 51). showed that HFSCs rapidly migrate from the bulge to the wound
These multipotent cells give rise to all epidermal lineages upon and contribute to epidermal repair (Fig. 2b). These data demon-
transplantation48–50,52. Lineage tracing using Blimp1-Cre47, Lgr6- strate that HFSCs are highly plastic during wound healing, similarly
CreER48,53 and Lrig1-CreER54 has confirmed that these cells main- to their expanded fate potential upon transplantation17,20,30,49,52.
tain the isthmus and sebaceous gland during homeostasis (Fig. 2a). Clonal analysis of IFESCs and committed progenitor cells fol-
In addition, Lrig1-expressing cells also give rise to cells of the infun- lowing injury of mouse tail skin showed that IFESCs are recruited
dibulum54 (Fig. 2a), whereas Gata6-expressing stem cells only con- to the wound, contribute to epidermal repair and persist up to 35
tribute to the maintenance of the sebaceous gland ducts but not days44 (Fig. 2b). By contrast, committed progenitors are initially
the gland itself during homeostasis50 (Fig. 2a). Altogether, these recruited, but their progeny do not remain in the wound long
data show that, during physiological conditions, skin stem cells term44. Additional lineage tracing with Dlx1-CreER and Slc1a3-
are confined to restricted compartments. Presently, the molecular CreER reporters, which mark slow-cycling and rapidly cycling stem
mechanisms that restrain the movement of these cells across dif- cells from different microdomains of tail and back skin IFE, demon-
ferent territories remain unclear. As in the intestine55, cell-specific strated that, upon wounding, both stem cell populations repopulate
expression of different guidance molecules might confine cell types the two IFE regions59. However, in the long term, both cell popula-
in specific territories. tions only persist in their region of origin and not in the region that

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a
Short-term tracing Long-term tracing

Stem cell
populations Markers CreER tracing

IFESC Itgα2 high

, Itgβ1 high
K14-CreER
IFE CP Inv, Lgr6 Inv-CreER
Lgr6-CreER
Ah-CreER

Infundibulum Lrig1 Lrig1-CreER

Homeostasis

Sebaceous gland Gata6 Gata6-CreER

ducts

Isthmus and Lrig1, Lgr6, Lrig1-CreER

sebaceous gland Blimp1, Plet1 Lgr6-CreER
Blimp1-Cre

Bulge K15, K19, Lgr5, Krt1-15-CrePR

CD34, Sox9, K19-CreER, Lgr5-CreER
Tcf3 Sox9-Cre, Sox9-CreER,
Tcf3-CreER

b
Wound Short-term tracing Long-term tracing
Repair

Fig. 2 | Skin epithelial stem cell populations during homeostasis and repair. a, Skin epithelial stem cells express specific markers and can be lineage traced
with CreER mouse strains (left table). IFESCs and committed progenitors are located in the basal layer of the IFE and give rise to suprabasal, differentiated
cells. Stem cells and committed progenitors can be traced using K14-CreER or Inv-CreER mouse strains induced at low dose, respectively. IFE committed
progenitors (CPs) also express Lgr6. Infundibulum stem cells are located in the upper part of the isthmus and express Lrig1. A population of sebaceous
gland duct stem cells expressing Gata6 are located at the entrance of the gland but only maintains the junctional zone. Isthmus and sebaceous gland stem
cells are basal cells located at the junction between the hair follicle and the gland, express Lrig1, Lgr6 and Blimp1 and give rise to the entire sebaceous gland
and the isthmus. Bulge stem cells are located in the permanent lowest portion of the hair follicle, express K15, K19, Lgr5, Cd34, Sox9 and Tcf3 and give rise
to the entire hair follicle. b, Upon wounding, both IFESCs and committed progenitors are recruited and contribute to tissue repair. Only IFESCs will reside in
the newly formed IFE long term. Isthmus, sebaceous gland and infundibulum stem cells are recruited, contribute to IFE repair and remain long term. Bulge
stem cells are recruited to the IFE and a small proportion can remain long term as IFESCs. Gata6-expressing sebaceous gland duct stem cells are recruited
to the IFE, migrate suprabasally, dedifferentiate and are re-established as IFESCs in the long term.

they migrate to during wound healing59. These observations suggest Moreover, similar to the contributions of hair follicles and the
that, during repair, all basal cells present some degree of plasticity, infundibulum in skin with hair, sweat gland duct progenitors help
a change in behaviour and functional contribution, but the wound to regenerate the injured epidermis in mouse paws61. Altogether,
does not reset the clock completely and cells keep a memory of their these studies suggest that the vacant niche created by an injury
original location and hierarchy. activates a broad range of stem cells to assume characteristics
Similarly to HFSCs, Lrig1-expressing and Lgr6-expressing stem that differ from their homeostatic roles. Additional studies will be
cells from the upper isthmus are mobilized following wounding and required to better understand the signals that activate distant stem
are possibly activated even more rapidly than HFSCs54. HFSCs have cells, respective timelines and the mechanisms that disrupt and
been assumed to be quickly lost during regeneration and to only re-establish the boundaries between skin compartments. It fur-
serve as a transient bandage that allows other stem cells from the ther remains unclear how differentiation programmes get rewired
IFE and upper isthmus/infundibulum to sustain long-term repair34. during wound healing and how the balance between proliferation,
However, a more recent study showed that the proportion of hair migration and differentiation is achieved.
follicle and Lrig1-derived cells located in the epidermis drops dra-
matically 3 weeks after an injury, whereas remaining cells can per- Migration, proliferation and compartmentalization. Epidermal
sist up to 1 year thereafter54 (Fig. 2b). The persistence of these cells injury is typically followed by increased keratinocyte proliferation5.
in the re-epithelialized IFE is proportional to the amount of stem Interestingly, proliferation is not observed at the wound edge but
cells labelled in the beginning and suggests a stochastic competition rather at a distance of 0.5–1.5 mm away from the edge9,10,62, in a pro-
between equipotent stem cells rather than a hard-wired process54. liferative zone that surrounds the wound. At the leading edge, kera-
Importantly, glabrous skin, such as the ventral (or palmar) part tinocytes do not proliferate but migrate as a cellular sheet9,10 (Fig. 3).
of the paw, heals correctly with slower kinetics than human Intravital microscopy during wound healing demonstrated that
skin, showing that HFSCs are dispensable for wound healing60. both basal and suprabasal layers migrate during wound healing10.

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0 day post-wound proliferation prevents wound closure and cell compression at the
leading edge in tail skin9. By contrast, proliferation is dispensable
for wound closure in the mouse ear epidermis10. However, cells also
display a more elongated shape in wounds with inhibited prolifera-
tion, suggesting a compensatory effect10. Differences in wound size
and region-specific dermal populations could explain the discrep-
ancies observed between the ear and tail IFE. However, in Rac1-
1 day post-wound
knockout mice with perturbed cell migration and elongation, a
Proliferation Migration defect in the orientation of cell division is evident, suggesting its
Mixed control by migration of the leading edge10. Altogether, these obser-
vations imply that cell migration at the leading edge comes first after
wounding and that the displacement of cells in this region triggers
orientated cell division of the cells following behind. Increased pro-
liferation can itself generate a surplus of migrating cells that later
push the leading edge towards the wound centre.
Transcriptional profiling of cells from migration and prolifera-
4 days post-wound tion zones indicated two molecularly distinct and transient regions9.
Proliferation Migration
Itga5, Flrt2, Gjb6,
EphB2, Pcdhs
Cald1, Fmnl2,
Fscn1, Nav2
Cells at the leading edge expressed transiently higher levels of
Mixed matrix metalloproteinases, pro-inflammatory molecules, genes
controlling the cytoskeleton, microtubule and actin remodelling,
Wnt5a Cxcl2 Inhba
Plau Cxcl3 ECM ligands and cell-adhesion molecules, such as integrin α​5 (ref. 9)
Il24 MMPs (Fig. 3). The constant size of the leading edge and its indepen-
Lama3
Lamb3
dence of wound size or skin area suggest that the signals controlling
Lamc2 marker expression are local and potentially propagated from cell to
Fn1
cell within the epidermis. The leading edge might act as a transient
scaffold enabling harmonious wound healing. By secreting a higher
14 days post-wound level of proteins that control ECM remodelling and blood clot dis-
solution, the leading edge might promote the progression of tissue
regeneration towards the wound centre and protect stem cells and
their progeny from tissue remodelling.
In addition, the acquired migratory phenotype of keratinocytes
displays some features of epithelial-to-mesenchymal transition,
including downregulation of cell-adhesion molecules, increased
motility and upregulation of epithelial-to-mesenchymal transition
Epithelial cells Fibroblasts Fibrin markers, such as Slug63,64. Whether epithelial-to-mesenchymal tran-
ECM
Proliferative cells Proliferative hub cells
sition is required for efficient wound healing or leading edge migra-
(collagen, elastin,etc)
tion will require further analysis.
Chemokines and
Leading edge cells Actin regulators cytokines

ECM components Adhesion and Stem cell population dynamics. During homeostasis, IFESCs and
cell junctions committed progenitors divide asymmetrically at the population level
to maintain a constant number of epidermal cells65. However, during
Fig. 3 | Epidermal migration, proliferation and compartmentalization wound healing, cell numbers need to increase to compensate for lost
during wound healing. Epithelial cells start to migrate into the wound bed cells until re-epithelialization is completed. Excess of renewal over
within 12 hours after injury. The day after wounding, IFE cells located close differentiation can be achieved by increasing symmetric renewal or
to the wound show an elongated shape towards the direction of the wound decreasing the proportion of cells that undergo differentiation, as dur-
(horizontal arrows) and are quiescent, whereas cells located at a distance ing oesophageal wound repair66 or in vitro culture of keratinocytes67.
start to proliferate, which leads to the establishment of a proliferative Upon tail injury, clonal analysis of K14-CreER (IFESCs and pro-
and a migrating leading edge compartment. Between these two zones, genitors) and Lrig1-CreER (infundibulum stem cells) mouse strains
a mixed region is observed containing both migrating and proliferative demonstrated streaks of labelled cells arising from single IFE or
cells. Four days after wounding, leading edge cells are compressed and infundibulum cells, both basal and suprabasal, that project towards
upregulate the expression of specific genes that promote inflammation and the wound centre9. IFE-derived clones decreased by more than 90%
regeneration. This gene signature is transient and disappears when the IFE during the first week, due to rapid terminal differentiation of commit-
is healed. Vertical arrows represent the movement of basal cells toward the ted progenitors, but overall cell ratios demonstrated that committed
differentiated layers. MMPs, matrix metalloproteinases. progenitors continued to divide mostly asymmetrically at the popula-
tion level9. The proportion of basal and suprabasal cells from Lrig1-
CreER-derived clones was similar to IFE-derived clones, although the
The speed of migration is greatest closer to the leading edge and size of the infundibulum-derived clones was slightly bigger9. Clonal
decreases thereafter10. At a distance of 0.5 mm from the edge, both persistence, clone size and the basal/suprabasal cell ratio were consis-
migration and proliferation co-occur10. In this mixed region, basal tent with a hierarchical model in which rare stem cells reside at the
cells are elongated towards the wound and orient their division in top of the hierarchy, dividing asymmetrically at a much more rapid
this direction10. In the tail epidermis, cells present at the leading pace than homeostasis and give rise to progenitors, so that the equi-
edge are initially elongated parallel to the direction of the wound, librium between proliferation and differentiation remains balanced.
suggesting active migration, but assume a perpendicular orienta- Irrespective of their initial locations, wounding seems to induce the
tion 2–4 days after wounding, possibly because they are pushed and activation of a minor stem cell population, whereas lineage hierarchy
compressed by cells behind9. Whether proliferation is necessary for and balance between self-renewal and differentiation of committed
cell migration remains unclear. Pharmacological inhibition of cell progenitors remain unchanged from homeostasis9.

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Recently, clonal analysis of the human skin epidermis was per- of Wntless, a gene required for the secretion of Wnt ligands, suppresses
formed after grafting in vitro reconstructed, genetically engineered WIHN, suggesting that keratinocyte-derived Wnt is essential82.
skin into a patient with a severe form of the genetic skin disorder Different mouse strains have different susceptibilities to WIHN83,84.
epidermolysis bullosa68. Sequencing of the integration site of the ret- Toll-like receptor 3 (Tlr3) levels are increased in mouse strains with
rovirus used to replace the mutated gene revealed that viral integra- enhanced WIHN, and double-stranded RNA is a key signal that trig-
tion in keratinocyte colonies originating from progenitors rapidly gers skin regeneration through Tlr3 (ref. 84). Msh homeobox 2 is also
decreased over time68. By contrast, the integration sites of the most crucial for WIHN85. Fibroblast growth factor 9, secreted by γ​δ​T cells,
clonogenic colonies derived from stem cells increased, supporting triggers Wnt expression by wound-induced fibroblasts, further
the notion that only human skin stem cell-derived colonies are able amplifying the Wnt signal required for WIHN. These data illustrate
to renew and expand long term in vivo, whereas progenitor cells the importance of a crosstalk between immune cells, fibroblasts and
possess limited potential to self-renew and revert back into a stem keratinocytes to enable successful WIHN86.
cell-like state68. Plasticity upon wound healing is also observed in other skin
lineages. In the dermis, myofibroblasts, located close to de novo-
Stem cell plasticity. When stem cells from the hair follicle and infun- formed hair follicles, are converted into adipocytes in large
dibulum are recruited to the IFE upon injury, they progressively wounds87. This cell-fate conversion depends on bone morphoge-
lose their initial identity and are reprogrammed to an IFE fate34. netic protein signalling originating from newly formed hair fol-
The molecular mechanisms responsible for this plasticity are still licles that activate the expression of Zfp423, a transcription factor
incompletely understood. In a comparison of chromatin landscapes that regulates adipocyte development87. Cell plasticity has also been
of injured IFE and homeostatic HFSCs and IFESCs, the wounded described in other epithelia, such as the mammary gland, lung
IFE exhibited a hybrid signature between HFSCs and IFESCs, in and intestinal epithelium88. It will be important to define whether
which the open chromatin regions were enriched for both IFESC generic mechanisms conserved across different tissues and species
(Klf5) and HFSC (Sox9) transcription factors12. This hybrid stage control cellular plasticity after lineage ablation and during tissue
called ‘lineage infidelity’ seems to ensure proper re-establishment of repair, inflammation or tumorigenesis.
the epidermal barrier12. Although this hybrid state is transient dur-
ing repair, it persists in skin cancer12,69. Crosstalk between stem cells and the niche. During wound repair,
Differentiated suprabasal epidermal cells are able to revert back fibroblasts are responsible for ECM synthesis in the dermis and for
to a stem cell state upon wounding70,71, a phenomenon also observed the fibrotic response leading to scar formation5. However, during
in airway epithelium after lineage ablation of basal stem cells72. embryonic development and in certain body locations, such as the
However, lineage tracing and photolabelling of suprabasal IFE cells oral cavity, wounds heal without forming scars89. The dermis of the
demonstrated that these cells cannot adopt a basal state again under mouse back skin is composed of fibroblasts of different develop-
wound-healing conditions9,10. Contrastingly, a population of Gata6- mental origin90,91. At least two fibroblastic lineages give rise to the
expressing cells residing in the isthmus, which during homeostatic upper (papillary fibroblasts, dermal papillae and erector pili muscle)
conditions give rise to the sebaceous duct, can be mobilized during and lower (reticular fibroblasts, preadipocytes and hypodermal adi-
wound healing to migrate towards the injured IFE and revert from a pocytes) dermis, respectively90. Upon wounding, fibroblasts of the
differentiated to a basal stem cell fate50. This reversion does not occur lower dermis are recruited first, followed by fibroblasts of the upper
immediately after injury, as the suprabasal cells require a few days dermis90 (Fig. 1). Reticular fibroblasts secrete the collagens respon-
to access the basal layer and undergo stem cell reprogramming50. sible for scar tissue formation and are unable to regenerate the hair
This intriguing observation raises the question of whether other dif- follicle after transplantation90. This observation may potentially
ferentiated epidermal cells are also able to revert back to a stem cell explain why de novo hair follicle formation rarely occurs during
state or whether this is a unique property of the Gata6-expressing wound healing. The upper papillary dermis is the only fibroblast lin-
population. It is possible that the timing of reversion is important eage competent to regenerate hair follicles after transplantation, but
and that experiments performed on the tail and ear epidermis it is recruited late during repair90. Interestingly, activation of Wnt–β​
induced the labelling of the suprabasal cells too early to observe the -catenin signalling in epidermal cells increases the recruitment of
reversion9,10. Further experiments will be necessary to identify the papillary fibroblasts and also the number of hair follicles regener-
mechanisms underlying this cellular plasticity and reprogramming ated in the wound bed90. By sharp contrast, inhibition of β​-catenin
of differentiated cells during wound healing. Other cases of dedif- in fibroblasts promotes hair follicle regeneration during wound
ferentiation have been previously described in the hair follicle73,74. healing and correlates with a decrease in the number of reticular
After depilation or laser ablation to induce the loss of bulge HFSCs, fibroblasts and an increase in the number of papillary fibroblasts92.
hair germ cells73 and infundibulum or sebaceous gland cells74 are In addition to different locations, two distinct fibroblastic lineages
able to repopulate the stem cell niche and establish functional can also be identified on the basis of the embryonic expression of
HFSCs. Similarly to skin, cells in the gut epithelium that are com- Engrailed-1 (En-1)91. The En-1-positive lineage of fibroblasts pro-
mitted to terminal differentiation can revert back to a progen- duces ECM composed of collagen type I and type III, becomes
itor-like state and contribute to tissue repair following injury75–77. more abundant postnatally and is responsible for fibrotic scarring
However, intestinal stem cells are required to ensure tissue repair after injury91. By contrast, the En-1-negative lineage becomes less
following ionizing radiation78, demonstrating that, despite the abil- abundant after birth but has a higher regenerative capacity and their
ity of committed cells to re-assume stemness, regular tissue-resident dominance during embryonic development might explain why
stem cells are essential for repair. embryos are able to regenerate scarless skin91,93. Of note, the pref-
The degree of damage can also influence cellular plasticity. In erential location of En-1-positive lineage fibroblasts in the reticular
relatively small wounds, re-epithelialization occurs without reform- dermis after birth suggests that they encompass the reticular popu-
ing hair follicles, whereas de novo hair follicle formation is apparent lations previously described90,91. Altogether, these data support the
in large wounds8. Lineage tracing confirmed that these de novo hair importance of surrounding dermal fibroblasts in skin regeneration.
follicles do not originate from HFSCs but from IFE cells8. Analogous A crosstalk between epidermal and immune cells also plays a
to hair follicle morphogenesis during embryonic development79–81, major role during wound healing. Interestingly, after epidermal
WIHN depends on Wnt signalling, as overexpression of Dickkopf stem cells have been challenged with an inflammatory stimulus, the
Wnt signalling pathway inhibitor 1 or β​-catenin deletion in IFE basal skin retains a memory of past inflammation and heals faster upon
cells prevents de novo hair follicle regeneration8. Epidermal deletion wounding. This memory is associated with chromatin remodelling

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that primes stem cells to respond more rapidly upon injury, in par- 8. Ito, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse
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