GRHL2 and AP2a coordinate early surface ectoderm lineage commitment during development.

Ectodermal dysplasias including skin abnormalities and cleft lip/palate result from improper surface ectoderm (SE) patterning. However, the connection between SE gene regulatory networks and disease remains poorly understood. Here, we dissect human SE differentiation with multiomics and establish GRHL2 as a key mediator of early SE commitment, which acts by skewing cell fate away from the neural lineage. GRHL2 and master SE regulator AP2a balance early cell fate output, with GRHL2 facilitating AP2a binding to SE loci. In turn, AP2a restricts GRHL2 DNA binding away from de novo chromatin contacts. Integration of these regulatory sites with ectodermal dysplasia-associated genomic variants annotated within the Biomedical Data Commons identifies 55 loci previously implicated in craniofacial disorders. These include ABCA4/ARHGAP29 and NOG regulatory regions where disease-linked variants directly affect GRHL2/AP2a binding and gene transcription. These studies elucidate the logic underlying SE commitment and deepen our understanding of human oligogenic disease pathogenesis.

Thy1 marks a distinct population of slow-cycling stem cells in the mouse epidermis.

The presence of distinct stem cells that maintain the interfollicular epidermis is highly debated. Here, we report a population of keratinocytes, marked by Thy1, in the basal layer of the interfollicular epidermis. We find that epidermal cells expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than basal epidermal progenitors and display significant expansion potential in vitro. Multicolor lineage tracing analyses and mathematical modeling reveal that Thy1+ basal keratinocytes do not compete neutrally alike interfollicular progenitors and contribute long-term to both epidermal replenishment and wound repair. Importantly, ablation of Thy1+ cells strongly impairs these processes, thus indicating the non-redundant function of Thy1+ stem cells in the epidermis. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair.

THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair.

Anchored cells of the basal epidermis constantly undergo proliferation in an overcrowded environment. An important regulator of epidermal proliferation is YAP, which can be controlled by both cell-matrix and cell-cell interactions. Here, we report that THY1, a GPI-anchored protein, inhibits epidermal YAP activity through converging molecular mechanisms. THY1 deficiency leads to increased adhesion by activating the integrin-ß1-SRC module. Notably, regardless of high cellular densities, the absence of THY1 leads to the dissociation of an adherens junction complex that enables the release and translocation of YAP. Due to increased YAP-dependent proliferation, Thy1-/- mice display enhanced wound repair and hair follicle regeneration. Taken together, our work reveals THY1 as a crucial regulator of cell-matrix and cell-cell interactions that controls YAP activity in skin homeostasis and regeneration.

Fetomaternal microchimerism in tissue repair and tumor development.

In various placental mammals, the bidirectional exchange of cells during pregnancy can lead to the acquisition of genetically unique cells that can persist in both mother and child for decades. Over the years, it has become increasingly clear that this phenomenon, termed fetomaternal microchimerism may play key roles in a number of biological processes. In this perspective, we explore the concept of fetomaternal microchimerism and outline how fetal microchimeric cells are detected and immunologically tolerated within the maternal setting. Moreover, we discuss undertakings in the field that hint at the significant plasticity of fetal microchimeric cells and their potential roles in promoting maternal wound healing. Finally, we explore the multifaceted roles of fetal microchimeric cells in cancer development and progression. A deeper understanding of fetomaternal chimerism in healthy and diseased states will be key toward developing more efficient anti-cancer treatments and regenerative therapies.

Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death.

Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.

Neural networks for computing and denoising the continuous nonlinear Fourier spectrum in focusing nonlinear Schrödinger equation.

We combine the nonlinear Fourier transform (NFT) signal processing with machine learning methods for solving the direct spectral problem associated with the nonlinear Schrödinger equation. The latter is one of the core nonlinear science models emerging in a range of applications. Our focus is on the unexplored problem of computing the continuous nonlinear Fourier spectrum associated with decaying profiles, using a specially-structured deep neural network which we coined NFT-Net. The Bayesian optimisation is utilised to find the optimal neural network architecture. The benefits of using the NFT-Net as compared to the conventional numerical NFT methods becomes evident when we deal with noise-corrupted signals, where the neural networks-based processing results in effective noise suppression. This advantage becomes more pronounced when the noise level is sufficiently high, and we train the neural network on the noise-corrupted field profiles. The maximum restoration quality corresponds to the case where the signal-to-noise ratio of the training data coincides with that of the validation signals. Finally, we also demonstrate that the NFT b-coefficient important for optical communication applications can be recovered with high accuracy and denoised by the neural network with the same architecture.

Blimp1+ cells generate functional mouse sebaceous gland organoids in vitro.

Most studies on the skin focus primarily on the hair follicle and interfollicular epidermis, whereas little is known regarding the homeostasis of the sebaceous gland (SG). The SG has been proposed to be replenished by different pools of hair follicle stem cells and cells that resides in the SG base, marked by Blimp1. Here, we demonstrate that single Blimp1+ cells isolated from mice have the potential to generate SG organoids in vitro. Mimicking SG homeostasis, the outer layer of these organoids is composed of proliferating cells that migrate inward, undergo terminal differentiation and generating lipid-filled sebocytes. Performing confocal microscopy and mass-spectrometry, we report that these organoids exhibit known markers and a lipidomic profile similar to SGs in vivo. Furthermore, we identify a role for c-Myc in sebocyte proliferation and differentiation, and determine that SG organoids can serve as a platform for studying initial stages of acne vulgaris, making this a useful platform to identify potential therapeutic targets.

Soliton content in the standard optical OFDM signal.

The nonlinear Schrödinger equation (NLSE) is often used as a master path-average model for fiber-optic transmission lines. In general, the NLSE describes the co-existence of dispersive waves and soliton pulses. The propagation of a signal in such a nonlinear channel is conceptually different from linear systems. We demonstrate here that the conventional orthogonal frequency-division multiplexing (OFDM) input optical signal at powers typical for modern communication systems might have soliton components statistically created by the random process corresponding to the information content. Applying the Zakharov-Shabat spectral problem to a single OFDM symbol with multiple subcarriers, we quantify the effect of the statistical soliton occurrence in such an information-bearing optical signal. Moreover, we observe that at signal powers optimal for transmission, an OFDM symbol incorporates multiple solitons with high probability. The considered optical communication example is relevant to a more general physical problem of the generation of coherent structures from noise.

Caspase-3 Regulates YAP-Dependent Cell Proliferation and Organ Size.

Apoptosis culminates in the activation of caspase-3, which plays an important role in implementing the cell death program. Here, we reveal a non-apoptotic role of caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 is specifically activated in the proliferating cells of the sebaceous gland, but does not instruct cell elimination. Deletion or chemical inhibition of caspase-3 diminishes cell proliferation, decreases cell number and reduces sebaceous gland size in vivo. Exploring the underlying mechanism, we demonstrate that α-catenin is cleaved by caspase-3, thus facilitating the activation and nuclear translocation of yes-associated protein (YAP), a vital regulator of organ size. Accordingly, activation of caspase-3 leads to YAP-dependent organ size augmentation. Finally, we show that X-linked inhibitor of apoptosis protein (XIAP) serves as an endogenous feedback antagonist for the caspase-3/YAP signaling module. Taken together, we report here a molecular mechanism wherein the apoptotic machinery is refocused to regulate cell proliferation and orchestrate organ size.

Isolation of Stem Cells and Progenitors from Mouse Epidermis.

The epidermis consists of several distinct compartments including the interfollicular epidermis (IFE), sweat glands, sebaceous glands (SGs), and the hair follicle (HF). While the IFE and SGs are in a constant state of self-renewal, the HF cycles between phases of growth, destruction, and rest. The hair follicle stem cells (HFSCs) that fuel this perpetual cycle have been well described and are located in a niche termed the bulge. These bulge SCs express markers such as CD34 and Keratin 15 (K15), enabling the isolation of these cells. Here, we describe a powerful method for isolating HFSCs and epidermal progenitors from mouse skin utilizing fluorescence activated cell-sorting (FACS). Upon isolation, cells can be expanded and utilized in various in vivo and in vitro models aimed at studying the function of these unique cells. © 2017 by John Wiley & Sons, Inc.

Isolating Hair Follicle Stem Cells and Epidermal Keratinocytes from Dorsal Mouse Skin.

The hair follicle (HF) is an ideal system for studying the biology and regulation of adult stem cells (SCs). This dynamic mini organ is replenished by distinct pools of SCs, which are located in the permanent portion of the HF, a region known as the bulge. These multipotent bulge SCs were initially identified as slow cycling label retaining cells; however, their isolation has been made feasible after identification of specific cell markers, such as CD34 and keratin 15 (K15). Here, we describe a robust method for isolating bulge SCs and epidermal keratinocytes from mouse HFs utilizing fluorescence activated cell-sorting (FACS) technology. Isolated hair follicle SCs (HFSCs) can be utilized in various in vivo grafting models and are a valuable in vitro model for studying the mechanisms that govern multipotency, quiescence and activation.