Understanding skin morphogenesis across developmental, regenerative and evolutionary levels

1. MULTISCALE UNDERSTANDING OF SKIN MORPHOGENESIS

Morphogenesis produces anatomically elaborate and functionally diverse skin that is well adapted to dynamically interact with a complex and changing external environment.¹ Understanding the principles and the driving forces of morphogenesis is fundamental for developing deeper insights into the causes and the mechanisms of skin pathologies.² For instance, visible skin lesion patterns provide an “open book” to learn and understand many dermatological and systemic diseases.^{3, 4} Thus, studying skin morphogenesis, with pathogenesis in mind, can educate and inspire the development of new therapeutic strategies for skin diseases, particularly within the field of regenerative medicine.

Sengel and Dhouailly pioneered the use of cellular and tissue recombination approaches in studies on skin biology.⁵ Using chicken and mouse skin as experimental models, they uncovered the core morphogenetic principles behind ectodermal organ development. Early works showed how skin appendage identity can be converted between types—for example, between hairs and glands6 or between feathers and scales⁷ in response to retinoic acid. These works helped to recognize that morphologically distinct ectodermal organs share common developmental origin. In the 1990s, this line of research entered the molecular era, which led to the identification of the roles that major signalling pathways, including Hedgehog, FGF, WNT and BMP, play in ectodermal appendage type specification.^8–10 Other major works in the field at the time established how skin appendages, prominently hair follicles, can regenerate in cycles,¹¹ and uncovered the core stem cell populations¹² and the molecular controls necessary for their cyclic growth.¹³

Until recently, morphogenesis was considered to be a property of the developing embryonic skin and, thus, not relevant to adult skin biology. However, new studies indicate that regeneration in adult organs often involves cellular reprogramming and reactivation of developmental mechanisms.¹⁴ For example, research over the past decade has confirmed classic observations¹⁵ and has provided molecular‐level evidence that following wounding, adult mammalian skin is capable of reactivating embryonic‐like morphogenetic programs for regeneration of new hair follicles¹⁶ and dermal fat.¹⁷ Therefore, new knowledge about morphogenesis can be gleaned from comparative studies on embryonic development and embryonic‐like regeneration in adults. Such studies can reveal conserved core morphogenetic modules vs embryonic and adult state specific components. Moreover, comparative studies between species with low and high capacity for wound‐induced regeneration^18–21 can be a fruitful approach for identifying genetic, cellular and signalling determinants of clinically desirable high regenerative responses.

To better understand the mechanisms of morphogenesis necessitates studying them across interconnected developmental, regenerative and evolutionary levels (Figure 1). Indeed, the field of Evo‐Devo works at the intersection of evolutionary and developmental levels, and aims to uncover the origin, the functions, the genetic underpinning and the natural selection forces behind distinct morphogenetic programs. The seminal skin recombination studies between reptiles, birds and mammals predicted both shared and unique developmental modules regulating morphogenesis of scales, feathers and hairs.²² Thus, by learning from nature, Evo‐Devo studies help us get closer to finding answers to questions that include the origin of mammalian hair and avian feather as well as their evolutionary relatedness,^{23, 24} or the mechanisms behind periodic pattern formation during skin appendage morphogenesis.²⁵

Figure 1.

Skin morphogenesis across developmental, regenerative and evolutionary levels. Schematic representation of three levels for studying and understanding skin morphogenesis. Developmental level (centre, green) includes knowledge on the mechanisms of embryonic morphogenesis of skin and its multiple ectodermal appendage phenotypes. Regenerative level (top, blue) includes knowledge on the mechanisms of repair vs de novo regeneration of hair follicles in adult skin after wounding. Evolutionary level (bottom, red) includes knowledge on the shared and unique developmental modules that regulate formation of diverse ectodermal appendages across vertebrate clades.

Taken together, the field of skin morphogenesis has expanded tremendously with hundreds of relevant new papers now being published yearly. Here, we organize this thematic issue to highlight some of the recent advances in the fields of developmental, regenerative and comparative biology of the skin. Although not fully comprehensive given the wide breadth of the field, this issue provides balanced coverage of the research on major aspects of skin morphogenesis from different perspectives.

2. SYSTEMS BIOLOGY APPROACH TO STUDYING SKIN MORPHOGENESIS

At its core, the process of morphogenesis includes a sequence of cell fate acquisition events as well as “sculpturing” of the newly emerging cell collectives into elaborate anatomical structures. Given their complexity, to develop a deep understanding of any given morphogenetic process requires the use of multiple complementary experimental techniques that examine molecular and epigenetic profiles of cells, recognize cellular heterogeneity, track clonal histories and movements of cells within tissues, and analyse patterns and pattern‐inducing molecular events, among other events and parameters.^{26, 27} Not surprisingly, research on skin morphogenesis benefits from many classic as well as newly emerging experimental approaches. Genomic approaches, including single‐cell profiling, are becoming especially powerful new research tools, exemplified by the use of RNA‐sequencing in several papers in this issue.^{28, 29} Intravital imaging provides a platform to observe cellular behaviours in real time.³⁰ Another experimental approach that is becoming rapidly integrated into studies on skin is mathematical modelling, highlighted in two recent studies.^{31, 32} Unlike typical reductionist approaches that dissect essential components of a given system, modelling can provide a holistic understanding of how entire systems work.

3. SKIN MORPHOGENESIS ACROSS THE DEVELOPMENTAL LEVEL

Several articles in this issue study skin morphogenesis during development. Rendl’s group provides a refined classification guide to hair follicle morphogenesis.³³ It builds upon the seminal morphological guide proposed two decades ago by Paus et al,³⁴ and incorporates new molecular‐level knowledge from recent single‐cell RNA‐sequencing studies.^{35, 36} The study by Wong’s group reports on the role of GATA6 in regulating maintenance of the uppermost hair follicle compartment,³⁷ while another study explores the role of FAM83G, a putative effector of WNT and BMP signalling pathways, in hair follicle morphogenesis, differentiation and regenerative cycling.³⁸ Ezhkova’s group comprehensively compared the embryonic origin and signalling aspects of Merkel cell specification in hairless paw vs haired dorsal skin and reports on the regional differences.²⁸ Sundberg et al³⁹ preformed a large‐scale ageing phenotype screen of nail abnormalities across common inbred mouse strains and reveal previously unappreciated genotype‐dependent nail defect associations. Related to skin pigmentation, Watt’s group implicates the myosin superfamily member MYO10 in regulating normal bodywide pigment pattern formation,⁴⁰ while a review article comprehensively discusses the broader aspects of melanocyte lineage biology, including during skin development.⁴¹

4. SKIN MORPHOGENESIS ACROSS THE REGENERATIVE LEVEL

A number of articles in this issue examine the connection between morphogenesis and regeneration. One focus is centered on hair follicles—cyclically growing skin mini‐organs^{11, 42, 43} that can also efficiently repair after various injuries.⁴⁴ Hair growth cycle is regulated by a number of intra‐follicular signals,^45–47 but is also highly sensitive to signalling changes in the extra‐follicular skin macro‐environment.^{27, 48, 49} In this issue, Biernaskie’s group describes how skin wounding and the ensuing signalling changes alter dermal cell dynamics in hair follicles at the wound edge,⁵⁰ and two thought‐provoking articles by Paus et al discuss how cycling hair follicles engage in reciprocal signalling with skin‐resident macrophages⁵¹ and dermal adipocytes,⁵² as well as the functional implications of these interactions. Two review articles discuss the cellular and signalling mechanisms that allow hair follicles to repair in response to radiation and chemotherapy damage and resume an interrupted hair growth cycle.^{53, 54}

Wound‐induced regeneration is thought to be controlled by a complex signalling and epigenetic mechanism.⁵⁵ In this issue, Garza’s and Tumbar’s groups discuss the roles of non‐coding double‐stranded RNAs⁵⁶ and epigenetic reprogramming,⁵⁷ respectively, in enabling such regenerative behavior. The review article by Chuong et al⁵⁸ discusses the emerging evidence that in addition to molecular signals, regenerative responses in skin wounds are also profoundly controlled by mechanical cues. Two research papers examine the aspects of wound repair with high clinical relevance—regeneration of epidermal rete ridges in a Lanyu pig model⁵⁹ and keloid scar formation in a humanized keloid fibroblast mouse model.²⁹ Another study by Gurtner et al reports on age‐related changes to endogenous oxidative stress levels in mouse skin and how these changes affect myofibroblast differentiation and skin repair after wounding.⁶⁰

Regenerative wound healing can be facilitated with the tissue engineering approaches. Studies by Chuong’s group³² and Kwon’s group⁶¹ take a bioengineering approach to study aspects of human and mouse hair follicle morphogenesis, respectively, with the aspiration to identify a robust strategy to hair‐bearing skin reconstitution.

5. SKIN MORPHOGENESIS ACROSS THE EVOLUTIONARY LEVEL

Morphogenesis of ectodermal organs relies on a number of developmental modules which can be used, combined and modified to support the formation of diverse skin appendages across evolutionarily distant animal clades. To track the origin of skin appendages, in this issue, Dhouailly et al⁶² comprehensively explore the subject of follicular appendage evolution and propose that diverse appendages such as teeth, hair follicles, feather follicles as well as dermal scales in fish and epidermal scales in reptiles originate from a common ancestral placode‐like ectodermal appendage. As animals evolved, more and more complex integument organs evolved to adapt to the ever‐changing environment. Particularly notable in this respect are the diverse follicle and follicle‐like ectodermal appendages that endow animal skin with its many functions, including thermoregulation, camouflage, defense and mechano‐sensing to name a few.^{43, 63} Several articles in this issue examine evolutionary aspects of hair follicle neogenesis after wounding^{19, 20} and hair and feather follicle repair after genotoxic damage.⁵⁴ Mallarino and Barsh discuss the evolution and the mechanisms for periodic pigmentation pattern specification and implementation, focusing on stripe‐like patterns that evolved in a number of rodents.⁶⁴

Powerful insights on morphogenesis can be learned from emerging model organisms, whose skin has distinct anatomical or physiological features. In this issue, several works show how research on African spiny mice,^{19, 20, 57} African striped mice,⁶⁴ pigs⁵⁸ and dogs³⁸ can advance the understanding of skin morphogenesis and regeneration. Interestingly, the degree to which different mammalian species can activate wound‐induced neogenesis programs can vary substantially. Some species, notably African spiny mice (Acomys) , have evolved particularly robust regenerative responses to severe wounding.²¹ In this issue, Maden’s group outlines the current state of knowledge on the regenerative mechanisms in this emerging model organism,²⁰ and a comparative morphological study by Chuong’s group reports new insights on the differences in hair follicle development, cycling and wound‐induced neogenesis between Acomys and laboratory mouse models.¹⁹

By delving into this issue, one can appreciate a robust energy in the field. This issue also highlights the fact that future transformative research on some of the century‐long questions about skin morphogenesis will require a multiscale, Systems Biology‐level thinking as well as cutting‐edge experimental methodologies. Indeed, thanks to ever‐increasing cross‐discipline fertilization, we are already witnessing synergistic growth of the skin biology field. With this momentum, we can expect that the best is yet to come.