Homeostatic Conditions Research Articles

Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

A chronic low-grade inflammation within adipose tissue (AT) seems to be the link between obesity and some of its associated diseases. One hallmark of this AT inflammation is the accumulation of AT macrophages (ATMs) around dead or dying adipocytes, forming so-called crown-like structures (CLS). To investigate the dynamics of CLS and their direct impact on the activation state of ATMs, we established a laser injury model to deplete individual adipocytes in living AT from double reporter mice (GFP-labeled ATMs and tdTomato-labeled adipocytes). Hence, we were able to detect early ATM-adipocyte interactions by live imaging and to determine a precise timeline for CLS formation after adipocyte death. Further, our data indicate metabolic activation and increased lipid metabolism in ATMs upon forming CLS. Most importantly, adipocyte death, even in lean animals under homeostatic conditions, leads to a locally confined inflammation, which is in sharp contrast to other tissues. We identified cell size as cause for the described pro-inflammatory response, as the size of adipocytes is above a critical threshold size for efferocytosis, a process for anti-inflammatory removal of dead cells during tissue homeostasis. Finally, experiments on parabiotic mice verified that adipocyte death leads to a pro-inflammatory response of resident ATMs in vivo, without significant recruitment of blood monocytes. Our data indicate that adipocyte death triggers a unique degradation process and locally induces a metabolically activated ATM phenotype that is globally observed with obesity.

Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration

SummaryNecrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC.

Redox Buffering Capacity of Nanomaterials as an Index of ROS-Based Therapeutics and Toxicity: A Preclinical Animal Study.

Precise control of intracellular redox status, i.e., maintenance of the physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress), is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, and depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate-functionalized trimanganese tetroxide nanoparticles (C-Mn3O4 NPs) as a model nanosystem, we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in the animal model to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.

Loss of interleukin-10 receptor disrupts intestinal epithelial cell proliferation and skews differentiation towards the goblet cell fate.

Intestinal epithelial cells (IEC) are crucial for maintaining proper digestion and overall homeostasis of the gut mucosa. IEC proliferation and differentiation are tightly regulated by well described pathways, however, relatively little is known about how cytokines shape these processes. Given that the anti-inflammatory cytokine interleukin (IL)-10 promotes intestinal barrier function, and insufficient IL-10 signaling increases susceptibility to intestinal diseases like inflammatory bowel disease, we hypothesized that IL-10 signaling modulates processes underlying IEC proliferation and differentiation. This was tested using in vivo and in vitro IEC-specific IL-10 receptor 1 (IL-10R1) depletion under homeostatic conditions. Our findings revealed that loss of IL-10R1 drove lineage commitment toward a dominant goblet cell phenotype while decreasing absorptive cell-related features. Diminished IL-10 signaling also significantly elevated IEC proliferation with relatively minor changes to apoptosis. Characterization of signaling pathways upstream of proliferation demonstrated a significant reduction in the Wnt inhibitor, DKK1, increased nuclear localization of β-catenin, and increased transcripts of the proliferation marker, OLFM4, with IL-10R1 depletion. Phosphorylated STAT3 was nearly completely absent in IL-10R1 knockdown cells and may provide a mechanistic link between our observations and the regulation of these cellular processes. Our results demonstrate a novel role for IL-10 signaling in intestinal mucosal homeostasis by regulating proper balance of proliferation and IEC lineage fate.

Mechanisms of exTreg induction.

CD4+ CD25+ Foxp3+ Tregs play an important role in the maintenance of the immune system by regulating immune responses and resolving inflammation. Tregs exert their function by suppressing other immune cells and mediating peripheral self-tolerance. Under homeostatic conditions, Tregs are stable T-cell populations. However, under inflammatory environments, Tregs are converted to CD4+ CD25low Foxp3low cells. These cells are termed "exTreg" or "exFoxp3" cells. The molecular mechanism of Treg transition to exTregs remains incompletely understood. Uncertainties might be explained by a lack of consensus of biological markers to define Treg subsets in general and exTregs in particular. In this review, we summarize known markers of Tregs and factors responsible for exTreg generation including cytokines, signaling pathways, transcription factors, and epigenetic mechanisms. We also identify studies demonstrating the presence of exTregs in various diseases and sources of exTregs. Understanding the biology of Treg transition to exTregs will help in designing Treg-based therapeutic approaches.

Tissue-Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis.

ObjectiveTo compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA.MethodsIn‐depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high‐throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis.ResultsCompared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin‐17A (IL‐17A) and IL‐22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin‐homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue‐resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up‐regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22‐like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function.ConclusionTissue‐resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.

Stromal Cells Underlining the Paths From Autoimmunity, Inflammation to Cancer With Roles Beyond Structural and Nutritional Support.

Stromal cells provide structural support and nutrients in secondary lymphoid organs and non-lymphoid tissues. However, accumulating evidence suggests that a complex relationship exists between stromal cells and immune cells. Interactions between immune cells and stromal cells have been shown to influence the pathology of both autoimmunity and cancer. This review examines the heterogeneity of stromal cells within the lymph node and non-lymphoid tissues during both homeostatic and inflammatory conditions, in particular autoimmunity and cancer, with the goal of better understanding the complex and apparently paradoxical relationship between these two classes of diseases. The review surveys potential novel mechanisms involving the interactions between stromal cells and immune cells which may contribute to the development, pathology and underlying connection between autoimmunity and cancer, including potential pathways from autoimmune inflammation to either “hot” or “cold” tumors. These interactions may provide some insights to explain the rising incidence of both autoimmunity and cancer in young women in industrialized countries and have the potential to be exploited in the development of new interventions for preventions and treatments of both autoimmune diseases and cancer.

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.

CD40 Activity on Mesenchymal Cells Negatively Regulates OX40L to Maintain Bone Marrow Immune Homeostasis Under Stress Conditions.

BackgroundWithin the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development. This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio. This imbalance negatively impacts hematopoiesis, particularly in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown.MethodsWe studied the role of host radio-resistant cell-derived CD40 in restoring Teff/Treg homeostasis and proper B-cell development in a murine model of BMT. We characterized the host cellular source of CD40 and performed radiation chimera analyses by transplanting WT or Cd40-KO with WT BM in the presence of T-reg and co-infusing WT or - Cd40-KO BM-MSCs. Residual host and donor T cell expansion and activation (cytokine production) and also the expression of Treg fitness markers and conversion to Th17 were analyzed. The presence of Cd40+ BM-MSCs was analyzed in a human setting in correlation with the frequency of B-cell precursors in patients who underwent HSCT and variably developed acute graft-versus-host (aGVDH) disease.ResultsCD40 expression is nearly undetectable in the BM, yet a Cd40-KO recipient of WT donor chimera exhibited impaired B-cell lymphopoiesis and Treg development. Lethal irradiation promotes CD40 and OX40L expression in radio-resistant BM-MSCs through the induction of pro-inflammatory cytokines. OX40L favors Teff expansion and activation at the expense of Tregs; however, the expression of CD40 dampens OX40L expression and restores Treg homeostasis, thus facilitating proper B-cell development. Indeed, in contrast to dendritic cells in secondary lymphoid organs that require CD40 triggers to express OX40L, BM-MSCs require CD40 to inhibit OX40L expression.ConclusionsCD40+ BM-MSCs are immune regulatory elements within BM. Loss of CD40 results in uncontrolled T cell activation due to a reduced number of Tregs, and B-cell development is consequently impaired. GVHD provides an example of how a loss of CD40+ BM-MSCs and a reduction in B-cell precursors may occur in a human setting.

A Brief Review of Swimming Endurance and Chronic Stress Model for Evaluation of Adaptogenic activity

Stress is the disturbed homeostatic condition of the organism, and it is represented by non-specific response of the body to any demand imposed on it. Stress brings various changes in physiological condition of the organism, but various mechanism of the body will counteract to maintain homeostasis. In some situations, body’s adaptation to stress is like reward, which is responsible for improvement of body’s performance beyond its capacity. However if organism suffer strong acute or chronic stress, body is unable to maintain homeostasis. Under this condition, various types of diseases and disorders will develop, and even it may lead to death, if it is not managed at proper time. Hazardous stressful situation can be managed by using antistress agent or adaptogen. These agents improve physical and mental working capacity in severe stress circumstances. In different screening models for evaluation of adoptogenic activity, animals are challenged with acute or chronic stress conditions. Various stimulating, stress protective, tonic responses and biochemical markers were measured in evaluation of adoptogenic activity in these animal models.

Identification of a Stable, Non-Canonically Regulated Nrf2 Form in Lung Cancer Cells

Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2) transcription factor is recognized for its pro-survival and cell protective role upon exposure to oxidative, chemical, or metabolic stresses. Nrf2 controls a number of cellular processes such as proliferation, differentiation, apoptosis, autophagy, lipid synthesis, and metabolism and glucose metabolism and is a target of activation in chronic diseases like diabetes, neurodegenerative, and inflammatory diseases. The dark side of Nrf2 is revealed when its regulation is imbalanced (e.g., via oncogene activation or mutations) and under such conditions constitutively active Nrf2 promotes cancerogenesis, metastasis, and radio- and chemoresistance. When there is no stress, Nrf2 is instantly degraded via Keap1-Cullin 3 (Cul3) pathway but despite this, cells exhibit a basal activation of Nrf2 target genes. It is yet not clear how Nrf2 maintains the expression of its targets under homeostatic conditions. Here, we found a stable 105 kDa Nrf2 form that is resistant to Keap1-Cul3-mediated degradation and translocates to the nucleus of lung cancer cells. RNA-Seq analysis indicate that it might originate from the exon 2 or exon 3-truncated transcripts. This stable 105 kDa Nrf2 form might help explain the constitutive activity of Nrf2 under normal cellular conditions.

Metformin Activates Resident Neural Stem and Progenitor Cells, Reduces Inflammation and Improves Functional Recovery Following Spinal Cord Injury

The mammalian spinal cord contains a population of neural stem and progenitor cells (NSPCs) located within the periventricular region lining the central canal. These cells are primarily quiescent under homeostatic conditions and are activated following injury, however, this response is not sufficient to support functional recovery in mammals. We propose that enhancing resident NSPC activation is a promising approach to promote neurorepair and improve functional outcomes following spinal cord injury (SCI). The FDA-approved drug metformin has demonstrated efficacy in promoting functional recovery following brain injury through pleiotropic effects including NSPC activation, increased neurogenesis and oligodendrogenesis and modulation of the injury microenvironment including the inflammatory response. We hypothesize that metformin administration will promote functional recovery following SCI concomitant with activation of NSPCs and reduced inflammation. In a first series of in vitro experiments, we found that metformin significantly increases the size of the NSPC pool in females, but not males; increases neurogenesis in males and enhances oligodendrogenesis in both sexes. We next examined the effect of metformin treatment following SCI. Metformin was delivered to mice for 14 days starting immediately following SCI or starting at 7 days after SCI. Mice were tested on a skilled walking test and using gait analysis at 1 and 2 weeks following the start of metformin treatment. Mice that received metformin starting at the time of injury recovered motor function by 2 weeks post-treatment however, delayed administration was not effective at improving functional outcomes. Interestingly, the functional outcomes observed in both treatment paradigms were correlated with metformin's effect on inflammation, as measured by the numbers of Iba1+ microglia/macrophages. In mice that received metformin immediately post-SCI, Iba1+ cells were significantly reduced compared to vehicle-treated SCI mice. Delayed metformin treatment did not lead to reduced inflammation relative to vehicle-treated SCI mice. Together, these results support metformin as a viable therapeutic strategy to expand and enhance NSPCs, decrease inflammation and enhance functional outcomes when administered in the acute phase following SCI.

CD45-dependent regulation of B cell receptor signaling in atherosclerosis

Abstract Atherosclerosis is an inflammatory disease of the large and medium size arteries that is characterized by deposition of oxidized lipids within the vessel. While specific antigens are not well characterized, data show that the immune response is involved in atherogenesis. The role of B cells in atherosclerosis is B cell specific: FO B cells are proatherogenic, while B1 and MZ B cells serve as protective. B cell development, activation, and differentiation is dependent on B cell receptor signaling while important costimulatory molecules, like CD45, assist in the initial propagation of signal. To date, it is unknown how regulation of BCR signaling by CD45 impacts activation and functions of B cells in atherosclerosis. We took advantage of transgenic mice that express low levels of CD45 (CD45L/L) and examined the phenotype of CD45L/L B cells. We demonstrate that low expression of CD45 leads to attenuated BCR-induced B cell activation via the reduced Ca2+ flux and phosphorylation of ERK, BTK, and SYK kinase, while favoring MZ and B1 B cell differentiation in homeostatic conditions. To test the effects of B cells expressing low levels of CD45 in atherosclerosis, we performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient atherosclerotic prone mice. After 23–28 wks of western diet feeding, the CD45L/L vs WT B cell recipients had reduced lesion formation accompanied by increased MZ B cells and decreased germinal center formation. This suggests that attenuation of BCR signaling through CD45 affects B cell subset differentiation and activation and highlight a potential role of BCR-related signaling in regulation of immunity in atherosclerosis.

B cells in the mesenteric fat contribute to Crohn’s disease

Abstract Crohn’s disease [CD] is one of the two common forms of inflammatory bowel disease and it affects over half a million Americans. Like many other diseases marked by chronic inflammation, some patients with CD develop tertiary lymphoid organs [TLO] in regions of the gut with active disease. TLOs are organized clusters of adaptive immune cells, similar in function and structure to secondary lymphoid organs. Recently, we found B cell rich lymphoid aggregates in the mesenteric fat of CD patients positioned along dramatically remodeled lymphatic vessels, but their function, specifically of the B cells within these aggregates, is completely unknown. Using complementary imaging, flow cytometry, and single cell RNA sequencing approaches, we analyzed B cells present in the mesenteric fat from CD patients. Whereas B cells were essentially not present in the mesentery under homeostatic conditions, they were significantly increased in the inflamed mesenteric fat of CD patients. Single cell RNA sequencing data revealed differences in B cell populations in the mesenteric fat that potentially implicate B cells as contributing to lymphangiogenesis associated with TLOs. Simultaneously, we used a murine model of ileal inflammation to probe mechanism. Imaging and flow cytometry showed that the B cells in TLOs from TNFΔARE/+mice were comparable to the B cells from CD patients. Additionally, TNFΔARE/+/μMT mice, which lack B cells, further revealed that B cells may be required for the lymphatic remodeling seen in the mesentery.

Integrated OMICs unveil the bone-marrow microenvironment in human leukemia.

SummaryThe bone-marrow (BM) niche is the spatial environment composed by a network of multiple stromal components regulating adult hematopoiesis. We use multi-omics and computational tools to analyze multiple BM environmental compartments and decipher their mutual interactions in the context of acute myeloid leukemia (AML) xenografts. Under homeostatic conditions, we find a considerable overlap between niche populations identified using current markers. Our analysis defines eight functional clusters of genes informing on the cellular identity and function of the different subpopulations and pointing at specific stromal interrelationships. We describe how these transcriptomic profiles change during human AML development and, by using a proximity-based molecular approach, we identify early disease onset deregulated genes in the mesenchymal compartment. Finally, we analyze the BM proteomic secretome in the presence of AML and integrate it with the transcriptome to predict signaling nodes involved in niche alteration in AML.

Bidirectional intrinsic modulation of EEG band power time series and spectral components of heart rate variability.

Some hypotheses relate oscillations of EEG band power with autonomic processes derived from homeostatic control modulated by structures like the Central Autonomic Network and the Autonomic Nervous System. This research project studies the causal relationships between fluctuations of an autonomic process marker like the Heart Rate Variability (HRV) and the proposed EEG band power time series (BPts). To verify the existence of directional causal relationships, using Granger Causality (GC) test between HRV and BPts. Analyses were performed using two databases, of 9 and 14 subjects respectively. Experiments consisted of spontaneous breathing and a controlled breathing task (CBT). GC was tested over Intrinsinc Mode Functions of HRV derived from Empirical Mode Decomposition and BPts computed over α, β and γ bands. Positive GC tests were observed through each experimental task, channels, IMFs, EEG band, and direction. The largest number of positive GC relationships were found from BPts to HRV when testing, higher EEG band and IMF with lower spectral content. Opposite direction achieves lower total counts, but more related with IMFs of higher spectral content. Its presence also suggests that some homeostatic condition alters the BPts course given its increment under the CBT. It is important to notice that in both cases γ band achieves larger values for almost all of the studied conditions. Suggesting that such band has an important influence over HRV, but alterations on breathing condition also produce changes on BPts evolution, suggesting that the closed loop for homeostatic control alters neural dynamics at cortical level.

Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent

Monocytes develop in the bone marrow from the hematopoietic stem cells and represent heterogeneous phagocyte cells in the circulation. In homeostatic and inflammatory conditions, after recruitment into tissues, monocytes differentiate into macrophages and dendritic cells. Alcohol use causes about 3.3 million worldwide deaths per year, which is about 5.9% of all deaths. In the United States and Europe, alcohol use disorders represent the fifth leading cause of death. Females are more susceptible to alcoholic liver injury in both humans and mice. Strikingly, we still do not know how much of this difference in tissue injury is due to the differential effect of alcohol and its toxic metabolites on a) parenchymal or resident cells and/or b) immune response to alcohol. Therefore, we used a model of chronic alcohol exposure in mice to investigate the dynamics of monocytes, an innate immune cell type showed to be critical in alcoholic liver injury, by using immunophenotypic characterization. Our data reveal a sex-dimorphism of alcohol response of hepatic monocytes in female mice that is interferon receptor alpha dependent. This dimorphism could shed light on potential cellular mechanism(s) to explain the susceptibility of females to alcoholic immunopathogenesis and suggests an additional targetable pathway for alcoholic liver injury in females.

Gut as viral reservoir: lessons from gut viromes, HIV and COVID-19

The gut microbiota is composed of bacteria, fungi and viruses.1–3 While the presence and composition of the bacteriome have been extensively studied in recent years, the ‘dark matter’ of microbiomes...

CD200R1L is a functional evolutionary conserved activating receptor in human neutrophils.

Inhibitory and activating immune receptors play a key role in modulating the amplitude and duration of immune responses during infection and in maintaining immune balance in homeostatic conditions. The CD200 Receptor (CD200R) gene family in humans encodes one inhibitory receptor, CD200R1, and one putative activating member, CD200R1 Like (CD200R1L). It is demonstrated that CD200R1L is endogenously expressed by human neutrophils and activates cellular functions such as reactive oxygen species (ROS) production via Syk, PI3Kβ, PI3Kδ, and Rac GTPase signaling. Phylogenetic analysis shows that CD200R1L is present in many species among vertebrates, ranging from birds to primates, suggesting that evolutionary conservation of this receptor is critical for protection against co‐evolving pathogens. The duplication event that generated CD200R1L from CD200R occurred several times throughout evolution, supporting convergent evolution of CD200R1L. In our phylogenetic trees, CD200R1L has longer branch lengths than CD200R1 in most species, suggesting that CD200R1L is evolving faster than CD200R1. It is proposed that CD200R1L represents a hitherto uncharacterized activating receptor on human neutrophils.

Hair follicle stem cells as a skin-organizing signaling center during adult homeostasis.

Stem cells are the essential source of building blocks for tissue homeostasis and regeneration. Their behavior is dictated by both cell-intrinsic cues and extrinsic cues from the microenvironment, known as the stem cell niche. Interestingly, recent work began to demonstrate that hair follicle stem cells (HFSCs) are not only passive recipients of signals from the surroundings, but also actively send out signals to modulate the organization and function of their own niches. Here, we discuss recent findings, and briefly refer to the old, on the interaction of HFSCs and their niches with the emphasis on the outwards signals from HFSCs toward their niches. We also highlight recent technology advancements that further promote our understanding of HFSC niches. Taken together, the HFSCs emerge as a skin-organizing center rich in signaling output for niche remodeling during various stages of adult skin homeostasis. The intricate crosstalk between HFSCs and their niches adds important insight to skin biology that will inform clinical and bioengineering fields aiming to build complete and functional 3D organotypic cultures for skin replacement therapies.