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Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs during development, injury repair, and tumorigenesis to deliver oxygen, immune cells, and nutrients to tissues. Defects in angiogenesis occur in cardiovascular and inflammatory diseases, and chronic, non-healing wounds, yet treatment options are limited. Here, we provide a map of the early angiogenic niche by analyzing single-cell RNA sequencing of mouse skin wound healing. Our data implicate Langerhans cells (LCs), phagocytic, skin-resident immune cells, in driving angiogenesis during skin repair. Using lineage-driven reportersw, three-dimensional (3D) microscopy, and mouse genetics, we show that LCs are situated at the endothelial cell leading edge in mouse skin wounds and are necessary for angiogenesis during repair. These data provide additional future avenues for the control of angiogenesis to treat disease and chronic wounds and extend the function of LCs beyond their canonical role in antigen presentation and T cell immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Wound healing in adult mammalian tissues generally involves scarring instead of tissue regeneration. A study in this issue of Cell reveals that after injury, reindeer antler skin regenerates by priming regenerative genes in wound fibroblasts instead of forming a scar through an inflammatory gene program., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Many human diseases are caused by mutations in nuclear envelope (NE) proteins. How protein homeostasis and disease etiology are interconnected at the NE is poorly understood. Specifically, the identity of local ubiquitin ligases that facilitate ubiquitin-proteasome-dependent NE protein turnover is presently unknown. Here, we employ a short-lived, Lamin B receptor disease variant as a model substrate in a genetic screen to uncover key elements of NE protein turnover. We identify the ubiquitin-conjugating enzymes (E2s) Ube2G2 and Ube2D3, the membrane-resident ubiquitin ligases (E3s) RNF5 and HRD1, and the poorly understood protein TMEM33. RNF5, but not HRD1, requires TMEM33 both for efficient biosynthesis and function. Once synthesized, RNF5 responds dynamically to increased substrate levels at the NE by departing from the endoplasmic reticulum, where HRD1 remains confined. Thus, mammalian protein quality control machinery partitions between distinct cellular compartments to address locally changing substrate loads, establishing a robust cellular quality control system., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tissue repair in adult mammals lacks the regenerative ability of many tissues in other adult organisms like axolotl and newts. In this issue of Cell Stem Cell, Mascharak et al. use multi-omics approaches to identify an essential role for the transcription factor Trps1 in Yap-inhibited fibroblasts' tissue regenerative responses in murine skin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Fibroblasts are diverse mesenchymal cells that participate in tissue homeostasis and disease by producing complex extracellular matrix and creating signaling niches through biophysical and biochemical cues. Transcriptionally and functionally heterogeneous across and within organs, fibroblasts encode regional positional information and maintain distinct cellular progeny. We summarize their development, lineages, functions, and contributions to fibrosis in four fibroblast-rich organs: skin, lung, skeletal muscle, and heart. We propose that fibroblasts are uniquely poised for tissue repair by easily reentering the cell cycle and exhibiting a reversible plasticity in phenotype and cell fate. These properties, when activated aberrantly, drive fibrotic disorders in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mature adipocytes store fatty acids and are a common component of tissue stroma. Adipocyte function in regulating bone marrow, skin, muscle, and mammary gland biology is emerging, but the role of adipocyte-derived lipids in tissue homeostasis and repair is poorly understood. Here, we identify an essential role for adipocyte lipolysis in regulating inflammation and repair after injury in skin. Genetic mouse studies revealed that dermal adipocytes are necessary to initiate inflammation after injury and promote subsequent repair. We find through histological, ultrastructural, lipidomic, and genetic experiments in mice that adipocytes adjacent to skin injury initiate lipid release necessary for macrophage inflammation. Tamoxifen-inducible genetic lineage tracing of mature adipocytes and single-cell RNA sequencing revealed that dermal adipocytes alter their fate and generate ECM-producing myofibroblasts within wounds. Thus, adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes., Competing Interests: Declaration of Interests The authors have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The 2020 Canada Gairdner International Award has been awarded to Elaine Fuchs for her discovery of the role of adult skin stem cells in homeostasis, wound repair, inflammation, and cancer. These insights have established a foundation for basic knowledge on how adult stem cells form, maintain, and repair tissues and have provided the groundwork for additional exploration and discovery of pathways in other stem cell systems., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multiple stem cells maintain and repair tissues, yet how they communicate is not well understood. In this issue of Developmental Cell, Veniaminova et al. (2019) report that each sebaceous gland is maintained by local stem cells and that Notch signaling regulates multiple aspects of their function, revealing tissue homeostasis mechanisms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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 body's 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Regulatory T cells (T regs ) are emerging as an essential stem cell niche component that promotes wound repair in adipose, muscle, and lung tissues. Recently in Cell, Ali et al. (2017) report that skin resident T regs facilitate the proliferation and differentiation of hair follicle stem cells through Notch signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Adipocyte precursor cells generate lipid-filled mature adipocytes in multiple tissues during a high-fat diet and in skin during hair follicle growth. In Science, Plikus et al. report that myofibroblasts can generate lipid-filled adipocytes in large skin wounds that regenerate hair follicles, suggesting a new source of adipogenic progenitor cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tissue growth and maintenance requires stem cell populations that self-renew, proliferate, and differentiate. Maintenance of white adipose tissue (WAT) requires the proliferation and differentiation of adipocyte stem cells (ASCs) to form postmitotic, lipid-filled mature adipocytes. Here we use the dynamic adipogenic program that occurs during hair growth to uncover an unrecognized regulator of ASC self-renewal and proliferation, PDGFA, which activates AKT signaling to drive and maintain the adipogenic program in the skin. Pdgfa expression is reduced in aged ASCs and is required for ASC proliferation and maintenance in the dermis, but not in other WATs. Our molecular and genetic studies uncover PI3K/AKT2 as a direct PDGFA target that is activated in ASCs during WAT hyperplasia and is functionally required for dermal ASC proliferation. Our data therefore reveal active mechanisms that regulate ASC self-renewal in the skin and show that distinct regulatory mechanisms operate in different WAT depots., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In mammalian skin, multiple types of resident cells are required to create a functional tissue and support tissue homeostasis and regeneration. The cells that compose the epithelial stem cell niche for skin homeostasis and regeneration are not well defined. Here, we identify adipose precursor cells within the skin and demonstrate that their dynamic regeneration parallels the activation of skin stem cells. Functional analysis of adipocyte lineage cells in mice with defects in adipogenesis and in transplantation experiments revealed that intradermal adipocyte lineage cells are necessary and sufficient to drive follicular stem cell activation. Furthermore, we implicate PDGF expression by immature adipocyte cells in the regulation of follicular stem cell activity. These data highlight adipogenic cells as skin niche cells that positively regulate skin stem cell activity, and suggest that adipocyte lineage cells may alter epithelial stem cell function clinically., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Quiescent adult stem cells reside in specialized niches where they become activated to proliferate and differentiate during tissue homeostasis and injury. How stem cell quiescence is governed is poorly understood. We report here that NFATc1 is preferentially expressed by hair follicle stem cells in their niche, where its expression is activated by BMP signaling upstream and it acts downstream to transcriptionally repress CDK4 and maintain stem cell quiescence. As stem cells become activated during hair growth, NFATc1 is downregulated, relieving CDK4 repression and activating proliferation. When calcineurin/NFATc1 signaling is suppressed, pharmacologically or via complete or conditional NFATc1 gene ablation, stem cells are activated prematurely, resulting in precocious follicular growth. Our findings may explain why patients receiving cyclosporine A for immunosuppressive therapy display excessive hair growth, and unveil a functional role for calcium-NFATc1-CDK4 circuitry in governing stem cell quiescence.

Most epithelial tissues self-renew throughout adult life due to the presence of multipotent stem cells and/or unipotent progenitor cells. Epithelial stem cells are specified during development and are controlled by epithelial-mesenchymal interactions. Despite morphological and functional differences among epithelia, common signaling pathways appear to control epithelial stem cell maintenance, activation, lineage determination, and differentiation. Additionally, deregulation of these pathways can lead to human disorders including cancer. Understanding epithelial stem cell biology has major clinical implications for the diagnosis, prevention, and treatment of human diseases, as well as for regenerative medicine.

Epidermal lineage commitment occurs when multipotent stem cells are specified to three lineages: the epidermis, the hair follicle, and the sebaceous gland (SG). How and when a lineage becomes specified remains unknown. Here, we report the existence of a population of unipotent progenitor cells that reside in the SG and express the transcriptional repressor Blimp1. Using cell-culture studies and genetic lineage tracing, we demonstrate that Blimp1-expressing cells are upstream from other cells of the SG lineage. Blimp1 appears to govern cellular input into the gland since its loss leads to elevated c-myc expression, augmented cell proliferation, and SG hyperplasia. Finally, BrdU labeling experiments demonstrate that the SG defects associated with loss of Blimp1 lead to enhanced bulge stem cell activity, suggesting that when normal SG homeostasis is perturbed, multipotent stem cells in the bulge can be mobilized to correct this imbalance.

Skeletal muscle formation and growth require the fusion of myoblasts to form multinucleated myofibers or myotubes, but few molecules are known to regulate myoblast fusion in mammals. The transcription factor NFATc2 controls myoblast fusion at a specific stage of myogenesis after the initial formation of a myotube and is necessary for further cell growth. By examining genes regulated by NFATc2 in muscle, this study identifies the cytokine IL-4 as a molecular signal that controls myoblast fusion with myotubes. Muscle cells lacking IL-4 or the IL-4alpha receptor subunit form normally but are reduced in size and myonuclear number. IL-4 is expressed by a subset of muscle cells in fusing muscle cultures and requires the IL-4alpha receptor subunit on myoblasts to promote fusion and growth. These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth.