Christian Fernando Guerrero-Juarez

Dermal adipocytes protect against invasive Staphylococcus aureus skin infection

Skin infection triggers fat responses Obesity is associated with chronic inflammation, but does fat tissue offer protection during infection? Zhang et al. noticed that the fat layers in the skin of mice thickened after inoculation with the pathogenic bacterium Staphylococcus aureus (see the Perspective by Alcorn and Kolls). Mutant mice incapable of forming new fat cells were more susceptible to infection. The differentiating fat cells secreted a small-molecule peptide called cathelicidin, specifically in response to the infection. By contrast, mature fat cells produce less cathelicidin, and are thus less protective. Science, this issue p. 67; see also p. 26 The subcutaneous fat layer thickens during infection and stimulates adipocytes to secrete a protective peptide. [Also see Perspective by Alcorn and Kolls] Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423nur12 mice or in mice given inhibitors of peroxisome proliferator–activated receptor γ. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp−/− mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.

Regeneration of fat cells from myofibroblasts during wound healing

Hair follicles: Secret to prevent scars? Although some animals easily regenerate limbs and heal broken flesh, mammals are generally not so gifted. Wounding can leave scars, which are characterized by a lack of hair follicles and cutaneous fat. Plikus et al. now show that hair follicles in both mice and humans can convert myofibroblasts, the predominant dermal cell in a wound, into adipocytes (see the Perspective by Chan and Longaker). The hair follicles activated the bone morphogenetic protein (BMP) signaling pathway and adipocyte transcription factors in the myofibroblast. Thus, it may be possible to reduce scar formation after wounding by adding BMP. Science, this issue p. 748; see also p. 693 Hair follicles convert wound myofibroblasts to adipocytes through the bone morphogenetic protein signaling pathway, revealing a target to decrease scarring. Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro. Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.

Organ-Level Quorum Sensing Directs Regeneration in Hair Stem Cell Populations

Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair plucking, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Plucking hair at different densities leads to a regeneration of up to five times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α-secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells.

Organotypic Skin Culture

An organotypic culture system (OCS) allows for the in vitro growth of complex biological tissues in a way that replicates part of their normal physiology and function. Because epidermis and other skin components, such as hair follicles, can be readily maintained in vitro, OCSs have gained broad popularity in dermatological research. Compared with traditional “on-a-plastic” cultures, where individual dissociated cells quickly lose all but a few of their original in vivo properties, cells in OCSs can engage in elaborate behaviors, such as the growth of new hairs, which requires complex coordination of cell division, differentiation, and migration. OCSs enable human skin to be studied with approaches, such as genetic manipulations, that are otherwise unsafe and unethical in human subjects. As such, skin OCSs are powerful as an experimental platform in preclinical dermatological research, helping to validate mechanisms of diseases and test the therapeutic potential of candidate drugs. This article provides an overview of organotypic skin culture techniques with special emphasis on stratified epidermis and hair follicle in vitro systems.

Principles and mechanisms of regeneration in the mouse model for wound-induced hair follicle neogenesis.

Abstract Wound‐induced hair follicle neogenesis (WIHN) describes a regenerative phenomenon in adult mammalian skin wherein fully functional hair follicles regenerate de novo in the center of large excisional wounds. Originally described in rats, rabbits, sheep, and humans in 1940−1960, the WIHN phenomenon was reinvestigated in mice only recently. The process of de novo hair regeneration largely duplicates the morphological and signaling features of normal embryonic hair development. Similar to hair development, WIHN critically depends on the activation of canonical WNT signaling. However, unlike hair development, WNT activation in WIHN is dependent on fibroblast growth factor 9 signaling generated by the immune systems γδ T cells. The cellular bases of WIHN remain to be fully characterized; however, the available evidence leaves open the possibility for a blastema‐like mechanism wherein epidermal and/or dermal wound cells undergo epigenetic reprogramming toward a more plastic, embryonic‐like state. De novo hair follicles do not regenerate from preexisting hair‐fated bulge stem cells. This suggests that hair neogenesis is not driven by preexisting lineage‐restricted progenitors, as is the case for amputation‐induced mouse digit tip regeneration, but rather may require a blastema‐like mechanism. The WIHN model is characterized by several intriguing features, which await further explanation. These include (1) the minimum wound size requirement for activating neogenesis, (2) the restriction of hair neogenesis to the wounds center, and (3) imperfect patterning outcomes, both in terms of neogenic hair positioning within the wound and in terms of their orientation. Future enquiries into the WIHN process, made possible by a wide array of available skin‐specific genetic tools, will undoubtedly expand our understanding of the regeneration mechanisms in adult mammals.

Epigenetic control of skin and hair regeneration after wounding

Skin wound healing is a complex regenerative phenomenon that can result in hair follicle neogenesis. Skin regeneration requires significant contribution from the immune system and involves substantial remodelling of both epidermal and dermal compartments. In this viewpoint, we consider epigenetic regulation of reepithelialization, dermal restructuring and hair neogenesis. Because little is known about the epigenetic control of these events, we have drawn upon recent epigenetic mapping and functional studies of homeostatic skin maintenance, epithelial–mesenchymal transition in cancer, and new works on regenerative dermal cell lineages and the epigenetic events that may shape their conversion into myofibroblasts. Finally, we speculate on how these various healing components might converge for wound‐induced hair follicle neogenesis.

Hair Follicle Signaling Networks: a Dermal Papilla Centric Approach

Functional testing of dermal papilla (DP) signaling inputs into hair follicle (HF) morphogenesis and regeneration is becoming possible with the advent of new Cre lines. Targeted deletion of the signature genes in early DP precursors has revealed significant signaling redundancy during HF morphogenesis. Furthermore, the DP lineage commitment program can be exploited for generating highly inductive DP cells to be used in HF bioengineering assays.

A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning

The control principles behind robust cyclic regeneration of hair follicles (HFs) remain unclear. Using multi-scale modeling, we show that coupling inhibitors and activators with physical growth of HFs is sufficient to drive periodicity and excitability of hair regeneration. Model simulations and experimental data reveal that mouse skin behaves as a heterogeneous regenerative field, composed of anatomical domains where HFs have distinct cycling dynamics. Interactions between fast-cycling chin and ventral HFs and slow-cycling dorsal HFs produce bilaterally symmetric patterns. Ear skin behaves as a hyper-refractory domain with HFs in extended rest phase. Such hyper-refractivity relates to high levels of BMP ligands and WNT antagonists, in part expressed by ear-specific cartilage and muscle. Hair growth stops at the boundaries with hyper-refractory ears and anatomically discontinuous eyelids, generating wave-breaking effects. We posit that similar mechanisms for coupled regeneration with dominant activator, hyper-refractory, and wave-breaker regions can operate in other actively renewing organs. DOI: http://dx.doi.org/10.7554/eLife.22772.001

Anatomical, Physiological, and Functional Diversity of Adipose Tissue

Adipose tissue depots can exist in close association with other organs, where they assume diverse, often non-traditional functions. In stem cell-rich skin, bone marrow, and mammary glands, adipocytes signal to and modulate organ regeneration and remodeling. Skin adipocytes and their progenitors signal to hair follicles, promoting epithelial stem cell quiescence and activation, respectively. Hair follicles signal back to adipocyte progenitors, inducing their expansion and regeneration, as in skin scars. In mammary glands and heart, adipocytes supply lipids to neighboring cells for nutritional and metabolic functions, respectively. Adipose depots adjacent to skeletal structures function to absorb mechanical shock. Adipose tissue near the surface of skin and intestine senses and responds to bacterial invasion, contributing to the bodys innate immune barrier. As the recognition of diverse adipose depot functions increases, novel therapeutic approaches centered on tissue-specific adipocytes are likely to emerge for a range of cancers and regenerative, infectious, and autoimmune disorders.

Emerging nonmetabolic functions of skin fat

Although the major white adipose depots evolved primarily to store energy, secrete hormones and thermo-insulate the body, multiple secondary depots developed additional specialized and unconventional functions. Unlike any other fat tissue, dermal white adipose tissue (dWAT) evolved a large repertoire of novel features that are central to skin physiology, which we discuss in this Review. dWAT exists in close proximity to hair follicles, the principal appendages of the skin that periodically grow new hairs. Responding to multiple hair-derived signals, dWAT becomes closely connected to cycling hair follicles and periodically cycles itself. At the onset of new hair growth, hair follicles secrete activators of adipogenesis, while at the end of hair growth, a reduction in the secretion of activators or potentially, an increase in the secretion of inhibitors of adipogenesis, results in fat lipolysis. Hair-driven cycles of dWAT remodelling are uncoupled from size changes in other adipose depots that are controlled instead by systemic metabolic demands. Rich in growth factors, dWAT reciprocally signals to hair follicles, altering the activation state of their stem cells and modulating the pace of hair regrowth. dWAT cells also facilitate skin repair following injury and infection. In response to wounding, adipose progenitors secrete repair-inducing activators, while bacteria-sensing adipocytes produce antimicrobial peptides, thus aiding innate immune responses in the skin.