wound healing and skin regeneration - cshl...

Wound Healing and Skin Regeneration

Makoto Takeo1,2, Wendy Lee1,2, and Mayumi Ito1,2

1The Ronald O. Perelman Department of Dermatology, New York University, School of Medicine,New York, New York 10016

2Department of Cell Biology, New York University, School of Medicine, New York, New York 10016

Correspondence: [email protected]

The skin is a complex organ consisting of the epidermis, dermis, and skin appendages,including the hair follicle and sebaceous gland. Wound healing in adult mammals resultsin scar formation without any skin appendages. Studies have reported remarkable examplesof scarless healing in fetal skin and appendage regeneration in adult skin following theinfliction of large wounds. The models used in these studies have offered a new platformfor investigations of the cellular and molecular mechanisms underlying wound healingand skin regeneration in mammals. In this article, we will focus on the contribution ofskin appendages to wound healing and, conversely, skin appendage regeneration followinginjuries.

The skin is an intricate structure composedof the epidermis and dermis, including the

subcutaneous fat, or dermal adipocyte layer.Environmental challenges to the barrier includepenetration of harmful UV rays from the sun,invasion of harmful pathogens, and evapora-tion of water. Importantly, the skin also protectsthe underlying organs, a function necessary forthe survival of the organism. As a protectiveshield for the body from the external environ-ment, the skin is constantly exposed to potentialinjury, and thus wound healing is a vital processfor the survival of all higher organisms. Epider-mal appendages such as hair follicles, nails, andsweat glands help maintain and protect the skinand their important roles in wound healingcontinue to be elucidated. Better understandingof the cellular and molecular mechanisms un-

derlying wound healing will ultimately allow usto influence and accelerate the wound repair/regeneration process. This will benefit severeburn patients and amputees, especially in casesof extensive tissue loss and scarring.

Wound healing is a conserved evolutionaryprocess among species and encompasses spa-tially and temporally overlapping processesincluding inflammation, blood clotting, and cel-lular proliferation and extracellular matrix(ECM) remodeling (Seifert et al. 2012b; Rich-ardson et al. 2013). However, the outcome ofwound healing in the skin differs between spe-cies. Some lower vertebrates including fish (ze-brafish) and amphibians (axolotl and Xenopus)possess the ability to perfectly regenerate skin.It is known that after full-thickness excisionalwounds in Xenopus froglets and axolotols, the

Editors: Anthony E. Oro and Fiona M. Watt

Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a023267

Cite this article as Cold Spring Harb Perspect Med 2015;5:a023267

1

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org

on June 7, 2020 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

http://perspectivesinmedicine.cshlp.org/

entire skin, including secretory appendages, re-generates (Yokoyama et al. 2011; Seifert et al.2012b). During this process, even the pigmenta-tion pattern of the skin can be fully re-established(Seifert et al. 2012b). Zebrafish skin can also re-cover its striped pigmentation pattern followingwounding, as well as regenerate subcutaneousadipocytes and scales during the healing process,making the regenerated skin almost indistin-guishable from the original one (Richardsonet al. 2013).

In contrast, it is challenging for adult mam-mals, including humans, to achieve such re-generation. Typically, wound healing in adultmammals results in scar tissue that lack skinappendages. Although scar formation can meetthe requirements of the skin’s fundamentalfunction in preventing infection and dehydra-tion, this process can also be unfavorable. Be-cause of its obviously distinct appearance fromthe original intact skin, the scar formed as aresult of injuries or burns can result in devas-tating cosmetic and psychological consequenc-es, reducing the quality of life of the individual.Furthermore, skin appendages are an integralpart of the skin’s biological and physiologicalfunction. For example, skin epithelial append-ages contribute epidermal cells for wound heal-ing. Additionally, the hair follicle and sebaceousgland confer additional roles for the skin as sen-sory and thermoregulatory organs (Chen etal. 1997; Li et al. 2011). Consequently, scar for-mation prevents the complete recovery of skinfunction. Thus, the ability to restore the skin toits original state is highly valued. Interestingly,studies have reported remarkable examples ofscarless healing in fetal skin and appendage re-generation in adult skin following the inflictionof large wounds. The models used in these stud-ies have offered a new platform for investiga-tions of the cellular and molecular mechanismsunderlying wound healing and skin regenera-tion in mammals. These may provide importantinsights into the regeneration of missing struc-tures and redevelopment of fully functionalskin. In this chapter, we will focus on the con-tribution of skin appendages to wound healingand, conversely, skin appendage regenerationfollowing injuries.

RE-EPITHELIALIZATION AND EPITHELIALSTEM CELLS

The mammalian epidermis is a stratified squa-mous epithelium whose maintenance relies onproliferation and differentiation of the basallayer of the epidermis. As basal epidermal cellsdifferentiate and move toward the surface, theygive rise to suprabasal cells and the granular lay-er and eventually terminally differentiate intoenucleated corneocytes composing the stratumcorneum. As the outermost layer of the organ-ism, the epidermis is constantly exposed to mul-tiple forms of injury. Failure to re-epithelializeinjured skin causes the loss of the barrier func-tion of the organ, dehydration, infection or evendeath. Hence, rapid closure of the wound siteby migration and proliferation of epithelial cellsis critical to restore the barrier function that isvital for organism survival. A vast amount ofevidence now shows that the presence and func-tion of resident epithelial stem cells in adult skinfuel the re-epithelialization process.

Mascre et al. (2012) used two distinct pro-moters: Keratin14 that targets basal cells in theepidermis including a progenitor populationthat proliferates and differentiates, and Invol-culin that solely targets a committed progeni-tor cell population. Following wounding, bothpopulations are recruited to the wound area butit is predominantly progeny of Keratin 14 ex-pressing cells that survive long term, in con-trast to progeny of Involculin expressing cellsthat were lost earlier. This study illustrates theimportance of relatively undifferentiated cellsin the basal layer of the skin epithelium, andtheir contribution to epidermal repair followinginjury.

Lineage tracing with mice that ubiquitous-ly labels all keratinocytes of follicular origin(Shh-Cre;R26R-lacZ) showed that follicular cellscan be converted to epidermal cells (Levy et al.2007). Several distinct progenitor populationslocated in the hair follicle, including the bulge,upper bulge, hair follicle junctional zone nextto the sebaceous gland and infundibulum haveall been shown to contribute to the regeneratingskin. Using label retaining techniques to tracethe fate of slow cycling stem cells in the skin,

M. Takeo et al.

2 Cite this article as Cold Spring Harb Perspect Med 2015;5:a023267

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



hair follicle stem cells located in the bulge areaof the hair follicle were shown to mobilize to theupper follicle (Taylor et al. 2000) and then to theskin epidermis after wounding (Tumbar et al.2004). Consistent with these findings, trans-plantation studies have also shown that thebulge region from R26-LacZ adult vibrissal fol-licles can contribute progenitors to reform thehair follicle, sebaceous gland, as well as the epi-dermis (Oshima et al. 2001). Subsequently, ge-netic tracing of Keratin 15 expressing epithelialstem cells located in the bulge/secondary hairgerm region of the hair follicle showed that thesecells migrate to the epidermis toward the centerof the wound following full-thickness exisionalwounds (Ito et al. 2005; Levy et al. 2005). Ge-netic ablation of K15þ cells does not result indefects in normal epidermal homeostasis sug-gesting that they only shift to epidermal cellsin response to wounding. This illustrates thatwounding perturbs epidermal homeostasis bycell depletion, resulting in recruitment of epi-thelial cells in the hair follicle that give rise toepidermal cells to promote re-epithelialization.Following migration to the epidermis, K15þ ep-ithelial stem cell progeny acquire an epider-mal phenotype based on biochemical marker

analysis. However, the observation that mostof these cells disappear in the wound epidermissuggests that hair follicle bulge stem cells areprimarily involved in the acute cell injury phaseof wound repair (Fig. 1).

Lrig1 was the first marker identified for thejunctional zone (isthmus) between the hair fol-licle bulge, sebaceous gland and infundibulum(Jensen et al. 2009). Lrig1 expressing cells cangive rise to all adult epidermal lineages in skinreconstitution assays (Jensen et al. 2009). Incontrast, more recent genetic labeling analysisrevealed that Lrig1þ cells within the piloseba-ceous unit contribute to neither the hair folli-cle nor the interfollicular epidermis, but solelythe sebaceous gland or infundibulum duringhomeostasis (Page et al. 2013). After wound-ing, Lrig1 cells originating from the piloseba-ceous compartment migrate to the wound areaand persist up to 1 year in the regenerating IFE,and contribute permanently to the regeneratingtissue following wounding (Page et al. 2013).Similarly, Lgr6-positive cells identified in theisthmus area are shown to contribute to re-epithelialization (Snippert et al. 2010). Isolationof Lgr6-positive cells enabled them to reconsti-tute all of the epithelial lineages of the skin

Dermal papilla

Sebaceous gland

Isthmus

Bulge

Lgr6

K15

Lrig1Shh

Gli1 LRCs

A B

Secondary hair germ

Figure 1. Contributions of hair follicle stem cells to re-epithelialization. (A) Schematic illustration of bulge stemcell markers that contribute to re-epithelialization. (B) Lineage tracing of K15þ hair follicle stem cells afterexcisional wound using K15-LacZ mice. LacZ-positive cells were not found in IFE at 2 d after wounding (rightpanel). At 5 d, LacZþ cells start to migrate from hair follicle to wound center (middle panel). At 8 d afterwounding, re-epithelialization is completed and about 26% of re-epithelialized cells are lacZþ (left panel).(From Ito et al. 2005; reprinted, with permission.)


Cite this article as Cold Spring Harb Perspect Med 2015;5:a023267 3

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



and form hair follicle bearing skin when com-bined with inductive dermal cells in transplan-tation assays. Genetic tracing showed that Lgr6þ

cells give rise to epidermis and participate inthe hair follicle formation seen in the center ofthe wound. Lgr6þ cells persisted long term in thewound area suggesting that these cells have theability to maintain or reacquire the self-renew-ing capacity following exit from their originalniche within the isthmus. These studies establishthat progenitors residing in compartments oth-er than the bulge including the isthmus andjunctional zone convert into self-sustaining epi-dermal stem cells in response to trauma. Fur-thermore, the study by Brownell et al. (2011)showed that Gli1þ upper bulge cells contributeto the epidermal healing to establish long-termprogenitors following wounding. Interestingly,following skin denervation, Gli1þ cells can stillcontribute to the initial re-epithelialization butthey are not maintained in the regenerated epi-dermis. These results suggest that Gli1þ K152

upper bulge cells depend on a perineural stemcell niche for their ability to adopt epidermalstem cell fate after wounding. These studies sug-gest that extrinsic niche derived signals may de-termine the ability of follicular keratinocytes tobecome long-term epidermal progenitors aftermigrating from the hair follicle. Currently, it isnot known how much the re-epithelialized areais occupied by epithelial stem cells nor how theyare patterned in the re-epithelialized layer. Un-derstanding these may provide a platform to in-vestigate mechanisms of how cells from distinctlineages show different persistence in the newepidermis. Moreover, understanding the extentof how the adult skin epidermis is capable ofregenerating stem cells will define whether re-epithelialization in wounded mammals repre-sents the true regeneration process.

Although these studies established that hairfollicle epithelial stem cells contribute to re-epithelialization, a recurring question has beenwhether the hair follicle is necessary for woundhealing of hair bearing skin. A study that ex-perimentally addressed this entailed woundingEdaraddcr/cr mice that lack hair follicles in thetail skin (Langton et al. 2008). They showed thatthe tail skin of these mutant mice do not close

their wounds as efficiently as control tail skincontaining hair follicles. However, after an ini-tial lag period, the wound re-epithelializes atthe same rate. From these results, it was con-cluded that hair follicle cells accelerate the onsetof wound healing but are not necessary forwound healing. The relevance of hair folliclesto wound healing was also shown by a study thatinvestigated the influence of hair cycle stages onthe rate of wound healing. Ansell et al. (2011)showed that wound-healing rates were differ-ent depending on the hair cycle stage, in whichwound healing was faster, during the anagenphase of hair follicle cycling in vivo. This waslikely caused by the extensive blood vessel net-work, relative immunosuppression, reductionin cell adhesion genes, and increase in develop-mental pathway genes by follicular epithelialcells during the anagen stage compared withthe telogen stage. This is consistent with anotherstudy that showed that anagen hair follicles pro-duce angiogenic factors (Mecklenburg et al.2000). More recently, it was shown that micedeficient for the proapoptotic Sept4/ARTS genehave elevated numbers of hair follicle stem cellsas a result of reduced apoptosis (Fuchs et al.2013), which normally occurs in the catagenphase (Ito et al. 2004). Sept4/ARTS2/2 micedisplay significant improvement in wound heal-ing. Furthermore, this phenotype depended onK15-expressing hair follicle stem cells as indi-cated by lineage tracing.

Taken together, these studies illustrate thevital function of hair follicles as a cellular reser-voir for healing skin and as a signaling centerthat affects the behavior of nonhair follicle cells.

SCARLESS WOUND-HEALING PROCESSIN MAMMALS

In association with re-epithelialization, the res-toration of dermis takes place by migration andproliferation of fibroblasts. The response of fi-broblasts during wound healing determines theoutcome of tissue repair. In response to wound-ing, macrophages and fibroblasts release growthfactors that lead to further fibroblast migrationand proliferation. They also release inflamma-tory cytokines to induce the immune response

M. Takeo et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



to protect against external pathogens in thewound. These fibroblasts also produce collagensand other extracellular matrix proteins to aid inwound repair. While collagen and ECM depo-sition are required to close the wound efficient-ly, they are also deleteriously responsible for fi-brosis and scarring of the skin. Recent studieshave shown an essential role for intradermaladipocytes in fibroblast activation and migra-tion (Schmidt and Horsley 2013), suggestingthat multiple cell types in the dermis functionto activate the fibroblast proliferation and mi-gration necessary to repair the dermis. Recently,transplantation and lineage tracing have iden-tified two distinct dermal lineages that give riseto the upper and lower dermis, respectively. Fol-lowing wounding, both cell types are recruitedto the wounded area. One population forms thelower dermis in the initial injury response. Incontrast, the progeny that gives rise to the upperdermis is recruited during re-epithelializationand provides an environment for new hair fol-licle formation in the wounded area. This studyillustrates the importance of the dermal contri-bution to not only wound healing, but also toappendage regeneration (Driskell et al. 2013).

In 1970, a seminal article reported that rab-bit fetuses can heal wounds without the appear-ance of scar formation (Somasundaram andPrathap 1970). Since then, similar observationshave been reported in other mammals, includ-ing sheep, mice, rats, and humans (Somasun-daram and Prathap 1970; Burrington 1971; So-pher 1972; Rowlatt 1979; Hallock 1985). InSomasundaram and Prathap’s study (Hallock1985), a 0.5-cm disc of skin of either newbornor fetal (14–25 d after gestation) rabbits wasexcised. In newborn rabbits, wound contractionand scab formation are observed by 6 days afterwounding, resulting in granulation tissue de-velopment and scar formation. In contrast, acompact layer of spindle-shaped cells, two tothree cells thick, initially covered the fetal woundsurface. There was no apparent sign of woundcontraction, subsequent granulation tissue de-velopment, or scar formation. These pioneeringstudies did not describe or discuss whether andhow skin appendage regeneration accompaniedthe scarless wound healing, presumably because

of limitations in distinguishing between embry-onic development processes of skin appendagesand wound-induced de novo regeneration ofskin appendages at that time.

Since then, scar-free wound healing of hu-man fetuses was reported in 1979 (Rowlatt1979), and subsequent efforts have been di-rected at investigating the mechanisms under-lying scar-free wound healing by comparing thewound-healing processes between scarless andscarring wounds in multiple animal models.A key difference identified in fetal wound heal-ing is a low inflammatory reaction owing to theabsence of a fully developed immune system.In scarless wounds, neutrophils, macrophages,and mast cells have differences in size and ma-turity when compared with scarring wounds(Satish and Kathju 2010; Wulff et al. 2012). In-triguingly, Urodeles such as newts, capable ofperfectly regenerating multiple organs includ-ing the skin and limb, are immunodeficientcompared with other amphibians such as Xeno-pus that show a more limited ability to regener-ate (reviewed by Cohen 1971). The correlationbetween the immune system and competencefor regeneration led to a traditional hypothesisin wound-healing studies: inflammation mayrestrict regeneration by promoting fibrosis andscar formation.

The inflammatory response marks one ofthe earliest responses in the adult skin to wound-ing stimuli, and a number of studies have shownthat immune cell infiltration and signaling playa key role in scar formation and fibrosis. Im-mune cells and macrophages accumulate at awound site not only to fight against invadingmicroorganisms but also to produce variousgrowth factors such as FGFs and TGF-b to guidere-epithelialization, fibroblast repopulation andECM remodeling. Therefore it is plausible thatscarring or fibrosis during skin repair is promot-ed by cytokines or growth factors produced bythe inflammatory response. However, a similarcocktail of growth factors sufficient to promotescar formation may also be provided by skinresident cells even in the absence of a well-devel-oped immune system. In contrast to the semi-nal work by Barbul et al., which showed thatimmunodeficient Foxn1 null adult mice that



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



lack T lymphocytes close wounds without scarformation (Barbul et al. 1989), subsequent stud-ies in other immunodeficient mouse mod-els, such as Rag1-deficient mice and SCID (se-vere combined immune deficiency) mice, whichlack both B and T lymphocytes, showed thatwounds on these mice heal with scar formation(Gawronska-Kozak et al. 2006). Similarly, it isreported that thymus-depleted mice and micetreated with immunosuppressants also healwith scar formation (Gawronska-Kozak et al.2006). These results suggest that scar formationis not merely dependent on the degree of thelymphocyte-mediated inflammatory responseto wounding.

In efforts to identify the distinct molecularcharacteristics in scarless wound healing, Danget al. (2003) analyzed the expression of matrixmetalloproteinases (MMP) and their inhibi-tor TIMPs in scarless wounds and scarringwounds in rats. They made full-thickness exci-sional wounds on the dorsum of E16 and E19fetal rats in which wounds heal without or withscars, respectively. They compared gene expres-sion of MMPs and TIMPs at 24, 48, and 72 hafter wounding and found that scarless woundshave greater MMP expression relative to TIMPsin wounds that heal with a scar. More recently,Colwell et al. made excisional wounds on thedorsal back skin of E17 fetal mice and 3-wk-old postnatal mice, respectively. They comparedgene expression profiles between scarless fetalwounds and scarring postnatal wounds by mi-croarray at 1, 12, and 24 h, and found that up-regulation of genes involved in DNA transcrip-tion and repair, cell-cycle regulation, proteinhomeostasis, and intracellular signaling is de-tected more rapidly in response to woundingin fetal wounds (Colwell et al. 2008). Addition-ally, comparisons of scarless fetal wounds andadult wounds report that one of the most prom-inent and consistent differences between thetwo is the high expression of TGF-b3 in mouseand rat fetus (Cowin et al. 2001; Soo et al. 2003).Shah et al. showed that administration of ex-ogenous TGF-b3 into the dermis at the marginsof a full-thickness wound for 3 days reducedmonocyte and macrophage accumulation inthe wound area, resulting in reduced scar for-

mation with decreased fibronectin and collagenI and III deposition in the early stages of woundhealing (Shah et al. 1995). These studies suggestthat production of TGF-b3 may be a key factorto achieving scar-free wound healing. These ba-sic animal studies pave the way to clinical trialsto control scar formation in humans, whichshow that injection of recombinant humanTGF-b3 after injury or surgical removal ofscar tissue significantly reduces scar formation(Occleston et al. 2008; So et al. 2011). Despitethese advancements, there is still no treatmentthat completely prevents scar formation and in-duces regeneration of skin appendages includ-ing hair follicles.

REGENERATION OF SKIN APPENDAGES—HAIR FOLLICLE NEOGENESIS

Several of the molecular and cellular events thatorchestrate mammalian wound healing havebeen elucidated over the past several years. How-ever, there is still a lack of therapeutic inter-ventions that lead to perfect scarless skin regen-eration that includes appendages in the adultskin. Research aimed to influence the woundrepair process to promote regenerative healingrequires experimental models in which molecu-lar and cellular interactions can be efficientlydissected. Previous studies established that denovo hair follicles form in the wound area byrecapitulating embryonic hair follicle develop-ment, illustrating the remarkable regenerativecapacity of the adult skin (Ito et al. 2007). More-over, this phenomenon occurred in normalwild-type mice and therefore serves as a power-ful model to study how growth and patterningmechanisms can be properly activated and usedto regenerate missing appendages.

Hair follicle formation typically only occursduring embryonic development under homeo-static conditions. During embryonic develop-ment, cellular interactions between epithelialand mesenchymal cells lead to the formationof a hair placode and dermal papilla, and theirreciprocal interactions lead to morphogenesisand growth of the hair follicle. Coordinated ac-tivation of several key signaling pathways in-cluding Wnt/b-catenin and BMP regulators is

M. Takeo et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



essential for this process (Fig. 2) (Millar 2002;Schmidt-Ullrich and Paus 2005; Myung and Ito2012; Sennett and Rendl 2012). Once the hairfollicle forms, hair is produced cyclically by in-teractions between epithelial stem cells in thehair follicle bulge/secondary hair germ areaand dermal papilla cells throughout life (Cotsa-relis et al. 1990; Kishimoto et al. 2000; Botch-karev et al. 2001; Ito et al. 2002, 2004; Rendl et al.2008; Greco et al. 2009; Zhang et al. 2009;Enshell-Seijffers et al. 2010; Garza et al. 2011;Clavel et al. 2012; Oshimori and Fuchs 2012;Myung et al. 2013).

Mouse models with small punch wounds(�6 mm) heal largely by contraction (notethat contraction accounts for �90% of repairof mouse skin), while hair follicles fail to regen-erate in the wound site (Ito et al. 2007). In con-trast, after a large wound is made on the backskin (1 cm2 in 3 wk old, or 2.25 cm2 in ,7 wkold), contraction stops before wound closureleaving a measurable wound scar area. Re-epi-thelialization of large wounds occurs approxi-mately 2 wk after wounding in adult mice. Re-markably, although there is a lack of hair follicles

in the wound area at the completion of re-epi-thelialization, de novo hair follicles are foundin this area 2–3 d after re-epithelialization. Itis unknown how hair follicle neogenesis occursonly in the center of the wounds and is absent inthe peripheral area of wounds. During hair fol-licle neogenesis, expression of several genes thatare required for embryonic hair follicle develop-ment, such as Wnt10b, Lef1, and Shh, were ob-served. Moreover, in transgenic mice in whichepithelial cells secrete the Wnt inhibitor, Dkk1,wound closure occurs normally, while hair neo-genesis is inhibited. Similar defects were alsoobserved in another transgenic mouse thatlacks epithelial Wntless (Wls) expression, whichis required for Wnt ligand secretion (Myunget al. 2013). In contrast, the number of regener-ated hair germs significantly increased in K14-Wnt7a transgenic mice that overexpress Wnt7ain the epidermis. These results suggest that thesecretion of Wnt ligands from the epidermispromotes hair follicle neogenesis in adult mice(Fig. 2).

A more recent study from Gay et al. (2013)showed the role of FGF9 secretion from gd-T

Morphogenesis

Wnt ligand(s)Epidermis

Dermis Unknown factorWnt activation

Wnt ligand(s)

Wnt activation

Noggin BMP-4 Fgf-7/10Hair germDermal papilla

E12.5–14.5 E14.5

Hair follicle neogenesis

After wounding After re-epithelialization

Wnt ligand(s)

Wnt activation

Wnt activationHair germ

Fgf-9 ?

Wnt-2

Fgf-9Wnt activation

γδ-T cellDermal fibroblast Dermal papilla

Eda/EdarShh ?

Figure 2. Schematic illustration of molecular mechanisms during hair follicle morphogenesis (top) and neo-genesis (bottom).



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



cells and activation of Wnt signaling in dermalfibroblasts on hair follicle neogenesis (Fig. 2).They found that following large full-thicknessexcisional wounds, gd-T immune cells accumu-late within the wound site and secrete FGF9 be-fore re-epithelialization. Subsequently, FGF-9induces Wnt2 expression in dermal fibroblasts,which in turn leads to activation of Wnt signal-ing in dermal fibroblast in an autocrine mannerand induces FGF-9 expression in Wnt-activateddermal fibroblasts. In mice that lack gd-T cells(Tcrb2/2 mice ) or FGF-9 expression specifi-cally in T cells (Lck-Cre:Fgf9 fl/fl mice), woundclosure occurs normally, while Wnt signaling isabrogated in dermal fibroblasts, resulting in de-creased hair neogenesis. These findings showedthat the interplay between immune cells andskin fibroblasts recruited to the wound site isessential to the activation of molecular pathwaysthat promote hair follicle regeneration. On theother hand, another study showed that applica-tion of prostaglandin (PGD2), an inflammatorymediator, inhibits hair neogenesis while newhair formation is enhanced in mice that lack areceptor for PGD2, GPR44 (Nelson et al. 2013).These results suggest that inflammatory media-tors involved in wound healing have the abil-ity to modulate hair follicle regeneration in thewound area.

Although de novo hair follicles formed inthe wound were repopulated with functionalepithelial stem cells that possess the ability todrive cyclical growth of the new hair follicles,most of the neogenic hairs were unpigmented(Ito et al. 2007; Chou et al. 2013). It is believedthat formation of unpigmented hair follicle wascaused by the lack of melanocytes in the woundarea. In the normal skin, melanocyte stem cells(McSCs), responsible for hair pigmentation, arelocated in the hair follicle bulge and secondaryhair germ niche together with epithelial stemcells (Nishimura et al. 2002). The coordinatedactivation of these two stem cell populationsthrough co-activation of Wnt signaling resultsin pigmented hair production (Rabbani et al.2011). McSCs in the hair follicles that surroundthe wound migrate upward and populate thewound epidermis (Fig. 3) (Chou et al. 2013).It was also found that the distribution of epi-

dermal melanocytes is restricted to the woundperiphery, and epidermal melanocytes are occa-sionally found in the wound center where hairneogenesis occurs. In instances where melano-cytes are able to migrate to the center, epidermalmelanocytes participate in hair neogenesis. Asde novo hair follicles develop, McSCs are re-es-tablished in the newly formed bulge, and thesehair follicles produce pigmented hair. These re-sults indicate that when melanocytes are presentin the region of the skin where de novo hairfollicle formation occurs, these cells can prop-erly interact with epidermal and dermal cellsto participate in hair follicle neogenesis afterwounding.

Recently, similar hair follicle neogenesis wasreported in another mouse strain, the Africanspiny mouse (Acomys) (Seifert et al. 2012a).Sixty percent of the total dorsal surface areaof these mice are torn up as a result of autotomyand regenerate pigmented hair follicles within30 d after autotomy. Acomys can also regener-ate hair follicles after 4 mm2 small wounds un-like other mice. Moreover, the wound-healingprocess of Acomys shared similar characteris-tics observed in mammalian fetuses, such asslow deposition of the extracellular matrix andhigh-level expression of collagen III. These ob-servations suggest that hair follicle neogenesismay occur more effectively when the wound-healing process is similar to what occurs in fe-tuses.

CONCLUDING REMARKS ANDREMAINING QUESTIONS

Previous studies have established the contribu-tion of skin appendages to wound healing. Howwounding stimuli recruit stem cells for re-epi-thelialization is not fully understood. Furtherunderstanding of the molecular mechanismsunderlying the plasticity of epithelial stem cellsin the hair follicle will be necessary to designstrategies to efficiently exploit stem cells to en-hance tissue regeneration during wound heal-ing. At the same time, it is now clear that woundstimuli can trigger the skin to engage embryon-ic programs to regenerate hair follicles in adultmice. The relationship between scarless heal-

M. Takeo et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



ing and the ability to regenerate epidermal ap-pendages in the wound site is currently unclear.Wound-induced scar formation and epidermalappendage regeneration likely share some com-mon signals or mechanisms. However, it is un-known how the mechanisms that lead to thesetwo distinct consequences of wound healingare synchronized. For example, it is still unclear

whether precluding scar formation is a prereq-uisite to permit the skin to regenerate its ap-pendage or whether the addition of morphoge-netic signals in the presence of scar formationcan promote epidermal appendage formation.To integrate our understanding of wound heal-ing and appendage regeneration, it will be im-portant to dissect how molecular signals that

McSCs

McSCs

Trp2-LacZ Trp2-LacZ

A

D

G

E

B C

F

45 d 46 d 28 d

80 d25 d11 d

Melanocytes

Plgmented hair

Re-epithelialization

Wound periphery Wounded site

Hair follicle neogenesis Hair follicle development

Bulb

Bulge Follicle-derived melanocytes

Trp2-LacZ

Figure 3. Contribution of hair follicle–derived melanocytes to hair follicle neogenesis. (A–C) Hair regenerationfrom newly formed hair follicle in wound area. Note that almost all hair lack pigment. (D) Distribution of hairfollicle derived melanocytes in the wound in Dct-LacZ reporter mice in which melanocyte including McSCs arelabeled with LacZ. Most of the epidermal melanocytes are restricted to the wound periphery, and only a fewmelanocytes are found in the center of wound where hair follicle neogenesis occurs (red dashed line). (E)Occasional pigmented hair regeneration. (F) Whole mount view of newly formed hair follicle that producepigmented hair. Note the presence of McSCs in the bulge. (G) Schematic illustration of the contribution of hairfollicle–derived melanocytes to hair follicle neogenesis. Scale bars, 1 mm. (A–C from Ito et al. 2007; repro-duced, with permission; D–G from Chou et al. 2013; reproduced, with permission.)



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



are activated at each stage of the wound-healingprocess influence the behavior of each skin celltype and how these signals ultimately promotescarring and/or appendage regeneration.

Interestingly, epidermal appendage regener-ation also impacts surrounding cells. This con-cept is illustrated by a study that showed thatepithelial stabilization of b-catenin in adultskin, known to trigger de novo hair follicle for-mation, confers embryonic characteristics tosurrounding dermal cells (Collins et al. 2011).These observations suggest that epidermal ap-pendage formation is not merely a result of re-generative healing, but may be allowing regen-erative healing of surrounding dermal cells.Importantly, on amputation of the mouse digittip, regeneration of underlying mesenchymalbone occurs only in association with nail regen-eration (Fig. 4) (Borgens 1982; Zhao and Neu-feld 1995; Mohammad et al. 1999; Takeo et al.2013). Wound healing following digit amputa-tions proximal to the visible nail plate lacks nailregeneration and ends with scarring. These stud-ies highlight the possibility that epidermal ap-pendage formation emits multiple morphogensthat signal to other cell types in a paracrine man-ner. Little is known about the interplay betweenheterotypic cells that coordinately orchestratewound healing and regeneration. Dissectingthe molecular crosstalk between epidermal ap-pendage regeneration and dermal repair mayprovide important clues to instruct dermal cellsto engage embryonic/regenerative programs

and reduce scarring. These future studies holdthe promise to develop novel and innovative ap-proaches to exploit our cumulative understand-ing of signals that govern epidermal appendageregeneration and wound healing.

ACKNOWLEDGMENTS

W.L. is supported by the NYU Kimmel StemCell Center and NYSTEM training GrantC026880. M.I. is supported by the U.S. NationalInstitutes of Health, National Institute of Ar-thritis and Musculoskeletal and Skin DiseasesGrant 1R01AR59768-01A1, and the EllisonMedical Foundation.

REFERENCES

Ansel DM, Kloepper JE, Thomason HA, Paus R, HardmanMJ. 2011. Exploring the “hair growth–wound healingconnection”: Anagen phase promotes wound re-epithe-lialization. J Invest Dermatol 131: 518–528.

Barbul A, Shawe T, Rotter SM, Efron JE, Wasserkrug HL,Badawy SB. 1989. Wound healing in nude mice: A studyon the regulatory role of lymphocytes in fibroplasia. Sur-gery 105: 764–769.

Borgens RB. 1982. Mice regrow the tips of their foretoes.Science 217: 747–750.

Botchkarev VA, Botchkareva NV, Nakamura M, Huber O,Funa K, Lauster R, Paus R, Gilchrest BA. 2001. Noggin isrequired for induction of the hair follicle growth phase inpostnatal skin. FASEB J 15: 2205–2214.

Brownell I, Guevara E, Bai CB, Loomis CA, Joyner AL. 2011.Nerve-derived sonic hedgehog defines a niche for hairfollicle stem cells capable of becoming epidermal stemcells. Cell Stem Cell 8: 552–565.

Regenerated digit

Alc

ian

blue

/aliz

arin

red

sta

inin

g

No regeneration

Distal amputation

A BProximal amputation

Amputated tip Amputated tip

Figure 4. Relationship between nail regeneration and digit regeneration. Alcian blue/alizarin red staining ofmouse digit at 5 weeks after distal (A), or proximal (B) amputation. When a digit is amputated at the distal level,both nail and underlying mesenchymal digit bone regenerates A, while neither nail nor digit bone regeneratesfrom proximal amputation B. (Panel B is from Takeo et al. 2013; reproduced, with permission.)

M. Takeo et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Burrington JD. 1971. Wound healing in the fetal lamb. JPediatr Surg 6: 523–528.

Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ,Cone RD. 1997. Exocrine gland dysfunction in MC5-R-deficient mice: Evidence for coordinated regulation ofexocrine gland function by melanocortin peptides. Cell91: 789–798.

Chou WC, Takeo M, Rabbani P, Hu H, Lee W, Chung YR,Carucci J, Overbeek P, Ito M. 2013. Direct migration offollicular melanocyte stem cells to the epidermis afterwounding or UVB irradiation is dependent on Mc1r sig-naling. Nat Med 19: 924–929.

Clavel C, Grisanti L, Zemla R, Rezza A, Barros R, Sennett R,Mazloom AR, Chung CY, Cai X, Cai CL, et al. 2012. Sox2in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft pro-genitors. Dev Cell 23: 981–994.

Cohen N. 1971. Amphibian transplantation reactions—Review. Am Zool 11: 193.

Collins CA, Kretzschmar K, Watt FM. 2011. Repro-gramming adult dermis to a neonatal state through epi-dermal activation of b-catenin. Development 138: 5189–5199.

Colwell AS, Longaker MT, Peter Lorenz H. 2008. Identifica-tion of differentially regulated genes in fetal wounds dur-ing regenerative repair. Wound Repair Regen 16: 450–459.

Cotsarelis G, Sun TT, Lavker RM. 1990. Label-retaining cellsreside in the bulge area of pilosebaceous unit: Implica-tions for follicular stem cells, hair cycle, and skin carci-nogenesis. Cell 61: 1329–1337.

Cowin AJ, Holmes TM, Brosnan P, Ferguson MW. 2001.Expression of TGF-b and its receptors in murine fetaland adult dermal wounds. Eur J Dermatol 11: 424–431.

Dang CM, Beanes SR, Lee H, Zhang X, Soo C, Ting K. 2003.Scarless fetal wounds are associated with an increasedmatrix metalloproteinase-to-tissue-derived inhibitor ofmetalloproteinase ratio. Plast Reconstr Surg 111: 2273–2285.

Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K,Simons BD, Charalambous M, Ferron SR, Herault Y, Pav-lovic G, Ferguson-Smith AC, et al. 2013. Distinct fibro-blast lineages determine dermal architecture in skin de-velopment and repair. Nature 504: 277–281.

Enshell-Seijffers D, Lindon C, Kashiwagi M, Morgan BA.2010. b-Catenin activity in the dermal papilla regulatesmorphogenesis and regeneration of hair. Dev Cell 18:633–642.

Fuchs Y, Brown S, Gorenc T, Rodriguez J, Fuchs E, Steller H.2013. Sept4/ARTS regulates stem cell apoptosis and skinregeneration. Science 341: 286–289.

Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, StantonDC, Carrasco L, Spiegel JH, Tobias JW, et al. 2011. Baldscalp in men with androgenetic alopecia retains hair fol-licle stem cells but lacks CD200-rich and CD34-positivehair follicle progenitor cells. J Clin Invest 121: 613–622.

Gawronska-Kozak B, Bogacki M, Rim JS, Monroe WT, Ma-nuel JA. 2006. Scarless skin repair in immunodeficientmice. Wound Repair Regen 14: 265–276.

Gay D, Kwon O, Zhang Z, Spata M, Plikus MV, Holler PD,Ito M, Yang Z, Treffeisen E, Kim CD, et al. 2013. Fgf9 from

dermal gd-T cells induces hair follicle neogenesis afterwounding. Nat Med 19: 916–923.

Greco V, Chen T, Rendl M, Schober M, Pasolli HA, Stokes N,Dela Cruz-Racelis J, Fuchs E. 2009. A two-step mecha-nism for stem cell activation during hair regeneration.Cell Stem Cell 4: 155–169.

Hallock GG. 1985. In utero cleft lip repair in A/J mice. PlastReconstr Surg 75: 785–790.

Ito M, Kizawa K, Toyoda M, Morohashi M. 2002. Label-retaining cells in the bulge region are directed to cell deathafter plucking, followed by healing from the survivinghair germ. J Invest Dermatol 119: 1310–1316.

Ito M, Kizawa K, Hamada K, Cotsarelis G. 2004. Hair folliclestem cells in the lower bulge form the secondary germ, abiochemically distinct but functionally equivalent pro-genitor cell population, at the termination of catagen.Differentiation 72: 548–557.

Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, CotsarelisG. 2005. Stem cells in the hair follicle bulge contribute towound repair but not to homeostasis of the epidermis.Nat Med 11: 1351–1354.

Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, Cotsarelis G.2007. Wnt-dependent de novo hair follicle regenerationin adult mouse skin after wounding. Nature 447: 316–320.

Jensen KB, Collins CA, Nascimento E, Tan DW, Frye M,Itami S, Watt FM. 2009. Lrig1 expression defines a dis-tinct multipotent stem cell population in mammalianepidermis. Cell Stem Cell 4: 427–439.

Kishimoto J, Burgeson RE, Morgan BA. 2000. Wnt signalingmaintains the hair-inducing activity of the dermal papil-la. Genes Dev 14: 1181–1185.

Langton AK, Herrick SE, Headon DJ. 2008. An extendedepidermal response heals cutaneous wounds in the ab-sence of a hair follicle stem cell contribution. J InvestDermatol 128: 1311–1318.

Levy V, Lindon C, Harfe BD, Morgan BA. 2005. Distinctstem cell populations regenerate the follicle and interfol-licular epidermis. Dev Cell 9: 855–861.

Levy V, Lindon C, Zheng Y, Harfe BD, Morgan BA. 2007.Epidermal stem cells arise from the hair follicle afterwounding. FASEB J 21: 1358–1366.

Li L, Rutlin M, Abraira VE, Cassidy C, Kus L, Gong S,Jankowski MP, Luo W, Heintz N, Koerber HR, et al.2011. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147: 1615–1627.

Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S,Sotiropoulou PA, Simons BD, Blanpain C. 2012. Distinctcontribution of stem and progenitor cells to epidermalmaintenance. Nature 489: 257–262.

Mecklenburg L, Tobin DJ, Muller-Rover S, Handjiski B,Wendt G, Peters EM, Pohl S, Moll I, Paus R. 2000. Activehair growth (anagen) is associated with angiogenesis. JInvest Dermatol 114: 909–916.

Millar SE. 2002. Molecular mechanisms regulating hair fol-licle development. J Invest Dermatol 118: 216–225.

Mohammad KS, Day FA, Neufeld DA. 1999. Bone growth isinduced by nail transplantation in amputated proximalphalanges. Calcif Tissue Int 65: 408–410.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Myung P, Ito M. 2012. Dissecting the bulge in hair regener-ation. J Clin Invest 122: 448–454.

Myung PS, Takeo M, Ito M, Atit RP. 2013. Epithelial Wntligand secretion is required for adult hair follicle growthand regeneration. J Invest Dermatol 133: 31–41.

Nelson AM, Loy DE, Lawson JA, Katseff AS, Fitzgerald GA,Garza LA. 2013. Prostaglandin D2 inhibits wound-in-duced hair follicle neogenesis through the receptor,Gpr44. J Invest Dermatol 133: 881–889.

Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M,Moriyama M, Jackson IJ, Barrandon Y, Miyachi Y, Nishi-kawa S. 2002. Dominant role of the niche in melanocytestem-cell fate determination. Nature 416: 854–860.

Occleston NL, Laverty HG, O’Kane S, Ferguson MW. 2008.Prevention and reduction of scarring in the skin by trans-forming growth factor b3 (TGF-b3): From laboratorydiscovery to clinical pharmaceutical. J Biomater Sci PolymEd 19: 1047–1063.

Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y.2001. Morphogenesis and renewal of hair follicles fromadult multipotent stem cells. Cell 104: 233–245.

Oshimori N, Fuchs E. 2012. Paracrine TGF-b signalingcounterbalances BMP-mediated repression in hair folli-cle stem cell activation. Cell Stem Cell 10: 63–75.

Page ME, Lombard P, Ng F, Gottgens B, Jensen KB. 2013.The epidermis comprises autonomous compartmentsmaintained by distinct stem cell populations. Cell StemCell 13: 471–482.

Rabbani P, Takeo M, Chou W, Myung P, Bosenberg M, ChinL, Taketo MM, Ito M. 2011. Coordinated activation ofWnt in epithelial and melanocyte stem cells initiates pig-mented hair regeneration. Cell 145: 941–955.

Rendl M, Polak L, Fuchs E. 2008. BMP signaling in dermalpapilla cells is required for their hair follicle-inductiveproperties. Genes Dev 22: 543–557.

Richardson R, Slanchev K, Kraus C, Knyphausen P, Eming S,Hammerschmidt M. 2013. Adult zebrafish as a modelsystem for cutaneous wound-healing research. J InvestDermatol 133: 1655–1665.

Rowlatt U. 1979. Intrauterine wound healing in a 20 weekhuman fetus. Virchows Arch A Pathol Anat Histol 381:353–361.

Satish L, Kathju S. 2010. Cellular and molecular character-istics of scarless versus fibrotic wound healing. DermatolRes Pract 2010: 790234.

Schmidt BA, Horsley V. 2013. Intradermal adipocytes me-diate fibroblast recruitment during skin wound healing.Development 140: 1517–1527.

Schmidt-Ullrich R, Paus R. 2005. Molecular principles ofhair follicle induction and morphogenesis. Bioessays 27:247–261.

Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM,Maden M. 2012a. Skin shedding and tissue regenerationin African spiny mice (Acomys). Nature 489: 561–565.

Seifert AW, Monaghan JR, Voss SR, Maden M. 2012b. Skinregeneration in adult axolotls: A blueprint for scar-freehealing in vertebrates. PLoS ONE 7: e32875.

Sennett R, Rendl M. 2012. Mesenchymal-epithelial interac-tions during hair follicle morphogenesis and cycling.Semin Cell Dev Biol 23: 917–927.

Shah M, Foreman DM, Ferguson MW. 1995. Neutralisationof TGF-b1 and TGF-b2 or exogenous addition of TGF-b3 to cutaneous rat wounds reduces scarring. J Cell Sci108: 985–1002.

Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH,Barker N, van de Wetering M, van den Born M, BegthelH, Vries RG, et al. 2010. Lgr6 marks stem cells in the hairfollicle that generate all cell lineages of the skin. Science327: 1385–1389.

So K, McGrouther DA, Bush JA, Durani P, Taylor L, SkotnyG, Mason T, Metcalfe A, O’Kane S, Ferguson MW. 2011.Avotermin for scar improvement following scar revisionsurgery: A randomized, double-blind, within-patient,placebo-controlled, phase II clinical trial. Plast ReconstrSurg 128: 163–172.

Somasundaram K, Prathap K. 1970. Intra-uterine healing ofskin wounds in rabbit foetuses. J Pathol 100: 81–86.

Soo C, Beanes SR, Hu FY, Zhang X, Dang C, Chang G, WangY, Nishimura I, Freymiller E, Longaker MT, et al. 2003.Ontogenetic transition in fetal wound transforminggrowth factor-b regulation correlates with collagen orga-nization. Am J Pathol 163: 2459–2476.

Sopher D. 1972. The response of rat fetal membranes toinjury. Ann R Coll Surg Engl 51: 240–249.

Takeo M, Chou WC, Sun Q, Lee W, Rabbani P, Loomis C,Taketo MM, Ito M. 2013. Wnt activation in nail epithe-lium couples nail growth to digit regeneration. Nature499: 228–232.

Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM.2000. Involvement of follicular stem cells in formingnot only the follicle but also the epidermis. Cell 102:451–461.

Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE,Rendl M, Fuchs E. 2004. Defining the epithelial stemcell niche in skin. Science 303: 359–363.

Wulff BC, Parent AE, Meleski MA, DiPietro LA, SchrementiME, Wilgus TA. 2012. Mast cells contribute to scar for-mation during fetal wound healing. J Invest Dermatol132: 458–465.

Yokoyama H, Maruoka T, Aruga A, Amano T, Ohgo S, Shir-oishi T, Tamura K. 2011. Prx-1 expression in Xenopuslaevis scarless skin–wound healing and its resemblanceto epimorphic regeneration. J Invest Dermatol 131:2477–2485.

Zhang YV, Cheong J, Ciapurin N, McDermitt DJ, Tumbar T.2009. Distinct self-renewal and differentiation phases inthe niche of infrequently dividing hair follicle stem cells.Cell Stem Cell 5: 267–278.

Zhao W, Neufeld DA. 1995. Bone regrowth in young micestimulated by nail organ. J Exp Zool 271: 155–159.

M. Takeo et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



2015; doi: 10.1101/cshperspect.a023267Cold Spring Harb Perspect Med Makoto Takeo, Wendy Lee and Mayumi Ito Wound Healing and Skin Regeneration

Subject Collection The Skin and Its Diseases

InsightsMelanoma: Clinical Features and Genomic

Elena B. Hawryluk and Hensin TsaoDevelopment in the MouseModeling Cutaneous Squamous Carcinoma

Phillips Y. Huang and Allan BalmainWound Healing and Skin Regeneration

Makoto Takeo, Wendy Lee and Mayumi ItoNatural and Sun-Induced Aging of Human Skin

Laure Rittié and Gary J. Fisher

Development and Regeneration of the Hair FollicleEpithelial Stem and Progenitor Cells in The Dermal Papilla: An Instructive Niche for

Bruce A. Morgan

Advanced Treatment for Basal Cell Carcinomas

OroScott X. Atwood, Ramon J. Whitson and Anthony E.

Immunology and Skin in Health and DiseaseJillian M. Richmond and John E. Harris

Epidermal Polarity Genes in Health and Disease

M. NiessenFrederik Tellkamp, Susanne Vorhagen and Carien

and Adhesion in Epidermal Health and DiseaseDesmosomes: Regulators of Cellular Signaling

GreenJodi L. Johnson, Nicole A. Najor and Kathleen J.

Potentials, Advances, and LimitationsInduced Pluripotent Stem Cells in Dermatology:

Ganna Bilousova and Dennis R. Roop

in Adult Mammalian SkinMarkers of Epidermal Stem Cell Subpopulations

Kai Kretzschmar and Fiona M. Watt

The Genetics of Human Skin DiseaseGina M. DeStefano and Angela M. Christiano

Psoriasis

NestlePaola Di Meglio, Federica Villanova and Frank O. Disease

p53/p63/p73 in the Epidermis in Health and

Vladimir A. Botchkarev and Elsa R. FloresCell Therapy in Dermatology

McGrathGabriela Petrof, Alya Abdul-Wahab and John A. Receptors in Skin

Diversification and Specialization of Touch

David M. Owens and Ellen A. Lumpkin

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved


http://perspectivesinmedicine.cshlp.org/cgi/collection/

http://perspectivesinmedicine.cshlp.org/cgi/collection/


wound healing and skin regeneration - cshl...

Documents