Faculty Bibliography

BACKGROUND:As the incidence of frontal fibrosing alopecia (FFA) continues to rise, there is a need for an optimal treatment algorithm for FFA. OBJECTIVE:To produce an international consensus statement on the treatment modalities and prognostic indicators of FFA. METHODS:Sixty-nine hair experts from six continents were invited to participate in a three-round Delphi process. The final stage was held as a virtual meeting facilitated via Zoom. The consensus threshold was set at ≥66%. RESULTS:Of 365 questions, expert consensus was achieved in 204 (56%) questions following completion of the three rounds. Three additional questions were included at the final meeting. The category with the strongest consensus agreement was disease monitoring (9; 100%). Questions pertaining to physical therapies achieved the least category consensus (15; 40%), followed by systemic therapy (45; 43%). LIMITATIONS/CONCLUSIONS:The study lacked sufficient representation from Africa and South America. CONCLUSION/CONCLUSIONS:SOFFIA highlights areas of agreement and disagreement among experts. Robust research is warranted to provide evidence-based treatment recommendations.

We sought to identify clinically relevant regulators of hair follicle inflammation by conducting a human genetic study of hidradenitis suppurativa (HS), a prevalent, understudied, inflammatory disease with limited effective treatments. We performed a GWAS with 6,300 cases and identified 12 independent risk loci. Epigenetic and transcriptomic analyses of HS risk variants defined cell-specific gene regulatory programs. We experimentally validated a coherent gene module defined by upregulated SOX9, CXCR4, and CD74 co-expression that maps to aberrant epithelial structures in the skin. Pharmacological inhibition of CXCR4 implicates CD74 mediated regulation of PI3K/AKT and NF-κB signaling to calibrate inflammation, proliferation and apoptosis in keratinocytes. We next used genome-wide methods to interrogate shared polygenic architecture and identified new clinically and mechanistically relevant disease associations, including another condition that involves aberrant hair follicle remodeling, male pattern hair loss. Our results point towards CXCR4-CD74 signaling in HS and hair follicle homeostasis and suggest CXCR4 blockade as a new therapeutic strategy in HS.

The gastrointestinal tract is subjected to extensive mechanosensory stimulation during food ingestion. However, the identities of mechanosensory receptors in the enteric nervous system remain largely unknown. The pharynx of C. elegans is structurally and functionally analogous to the vertebrate foregut, but it contains only 20 neurons embedded among the muscles and epithelial cells of the organ. Here, we report that the DEG/ENaC family ion channel DEGT-1 is a proprioceptor of pharynx movement. DEGT-1 protein is expressed in four pharyngeal neurons (MI, M3, I4, and M5) and localized to their neuronal soma in direct contact with the collagenous pharyngeal basement membrane. degt-1 mutants display abnormally rapid feeding in the presence of food, causing global changes in lipid accumulation. degt-1 mutants also pump rapidly when pumping is induced by the presence of serotonin alone, suggesting that DEGT-1 is required for proprioception of pharyngeal pumping itself rather than for sensing ingested food. DEGT-1 is required in only two pharyngeal neurons (I4 and M5) to control pumping rate. I4 and M5 neurons show a DEGT-1-dependent calcium response. Taken together, these results suggest that DEGT-1 modulates pharyngeal pumping rate by relaying proprioceptive feedback generated by the shear force of the pharynx against its own basement membrane. Thus, mechanosensors in the enteric nervous system modulate organ function by detecting not only the forces from ingested contents but also the movements of the organ itself.

Cancer cells alter their mechanical properties in response to the rigidity of their environment. Here, we explored the implications of this environmental mechanosensing for anti-tumor immunosurveillance using single cell biophysical profiling and metastasis models. Cancer cells stiffened in more rigid environments, a biophysical change that sensitized them to cytotoxic lymphocytes. In immunodeficient mice, this behavior manifested in the outgrowth of stiffer metastatic cells in the rigid bone than in the soft lung, while in immunocompetent hosts, it led to preferential elimination of stiffer cancer cells and suppression of bone metastasis. Environmentally-induced cell stiffening and immune sensitization both required Osteopontin, a secreted glycoprotein that is upregulated during bone colonization. Analysis of patient metastases spanning mechanically distinct tissues revealed associations between environmental rigidity, immune infiltration, and cancer cell stiffness consistent with mechanically driven immunosurveillance. These results demonstrate how environmental mechanosensing modulates anti-tumor immunity and suggest a mechanoimmunological basis for metastatic site selection.

Brown adipose tissue (BAT) is an evolutionary innovation that enables placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure activates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (Slit3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We demonstrate that adipocyte progenitors secrete Slit3, which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which bind distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. We identify Plxna1 as a previously unrecognized receptor for Slit3-C and show that it is essential for sympathetic innervation and cold-induced neurite expansion in BAT. Moreover, we introduce bone morphogenetic protein 1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this work establishes a mechanistic framework for the coordinated regulation of sympathetic innervation and angiogenesis to enhance thermogenic function. The co-regulation of neurovascular expansion by distinct Slit3 fragments offers a bifurcated yet harmonized mechanism to ensure a synchronized BAT response to environmental challenges. Finally, this study provides the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

Despite bone's robust regenerative capacity, complications such as delayed union and nonunion affect 5-10% of fractures, with significant clinical and economic burdens. The rising incidence of fractures, particularly in an aging population, highlights the importance of optimizing fracture healing strategies. This review explores current therapies aimed at enhancing bone regeneration, focusing on 2 main categories: local biologic therapies and mechanical therapies. Local biologic treatments, including concentrated bone marrow aspirate, platelet-rich plasma, bone morphogenetic proteins, and platelet-derived growth factor, aim to stimulate osteogenesis at the fracture site. Therapies, such as electrical stimulation, low-intensity pulsed ultrasound, and extracorporeal shockwave therapy, are theorized to modify the mechanical environment to promote healing. Although these therapies show promise, variability in clinical outcomes emphasizes the need for further research to standardize protocols and refine treatment strategies. Overall, advancing our understanding of bone healing mechanisms will continue to drive innovation in fracture management, improving patient outcomes and reducing health care costs.

Cells adapt to proteostatic and metabolic stresses, in part, through stress activated eIF2α kinases that stimulate the translation of ATF4. Stress-induced ATF4 translation is regulated through elements at ATF4 mRNA's 5' leader. In addition to eIF2α kinases, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, we found that the mRNA cap-binding protein, 4EHP, was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. NELF-E mRNA, encoding a regulator of pol II-mediated transcription, was identified as a top interactor of 4EHP in a TRIBE (Targets of RNA Binding through Editing) screen. Quantitative proteomics analysis revealed that the knockdown of NELF-E or 4EHP commonly reduced several subunits of the 40S ribosome (RpS) and the eIF3 translation initiation factor. Moreover, reduction of NELF-E, 4EHP, RpS12, eIF3l, or eIF3h suppressed the expression of ATF4 and its target genes. These results uncover a previously unrecognized ATF4 regulatory network consisting of 4EHP and NELF-E that impacts proteostasis during normal development and in disease models.

Homeostasis of the nervous system is maintained by a population of resident neural stem cells (NSCs) retained in a state of reversible cell-cycle arrest called quiescence. Quiescent NSCs can resume proliferation in response to different physiological stimuli. Reactivation requires changes in gene expression, much of which is regulated at the epigenomic level. We mapped epigenomic changes in NSC chromatin during stem cell quiescence and reactivation in Drosophila in vivo. Contrary to expectations, chromatin accessibility is increased in quiescent NSCs. Surprisingly, genes crucial for cell-cycle progression are repressed while remaining within permissive H3K36me3-bound euchromatin. At the same time, genes necessary for cell-cell communication are derepressed by eviction of histone H1 and transition to an SWI/SNF-enriched active state. Our results reveal global expansion of accessible chromatin in quiescent NSCs without concomitant transcriptional activation. Strikingly, this process reverses upon reactivation, indicating that opening of chromatin is a quiescence-specific event.

Signaling interactions between the dermal papilla (DP) and neighboring stem cells in the hair germ (HGSCs) and bulge (BuSCs) regulate new follicle growth in the hair cycle. To study these interactions, the three populations had been profiled together by now-outdated microarrays or separately by bulk RNA-sequencing. Recent single-cell transcriptomics established signatures of DP, BuSCs and HGSCs, but low detection sensitivity limited the depth of gene expression discovery. Here, we define the transcriptomes of DP, BuSCs, HGSCs, epidermal, follicle and dermal fibroblast cells-after flow-sorting each population from four neighboring mouse back skin regions-to gain deeper insights into the unique gene expression programs of SCs and their instructive niche. With cross-comparisons of 56 whole-transcriptome measurements, we classify cell type-specific molecular signatures of enriched genes with unprecedented sensitivity. Joint analysis with signatures from 15 leading studies published in the last 20 years revealed many previously undescribed DP, BuSC and HGSC genes in mouse and human counterparts. With ligand-receptor mapping and CellChat analyses we then uncover comprehensive cell-cell communication insights. Finally, we provide a new installment of our Hair-Gel repository along with numerous signature and other gene tables for easy exploration of gene expression in hair follicle SCs and their niche.

BACKGROUND & AIM/UNASSIGNED:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health issue. Identifying factors that prevent hepatic lipid accumulation could inform new MASLD prevention or treatment strategies. We previously demonstrated that adipocyte microsomal triglyceride transfer protein (MTP) regulates intracellular lipolysis by inhibiting adipose triglyceride lipase activity. The aim of this study was to investigate the impact of adipose MTP deficiency on MASLD. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSION/UNASSIGNED:These findings highlight the importance of regulated FA flux from adipose tissue to the liver and the liver's adaptive capacity to utilize adipose-derived FAs in maintaining hepatic health. Modulation of adipocyte FA release may represent a therapeutic strategy to reduce hepatic steatosis. IMPACT AND IMPLICATIONS/UNASSIGNED:This study provides significant insights into the role of adipose-specific microsomal triglyceride transfer protein in regulating hepatic lipid metabolism and its potential implications for treating metabolic dysfunction-associated steatotic liver disease. By demonstrating that microsomal triglyceride transfer protein deficiency in adipose tissue leads to increased fatty acid oxidation and reduced hepatic steatosis through enhanced PPARα activation, the research underscores the importance of adipose-liver crosstalk in maintaining liver health. These findings suggest that targeting adipocyte fatty acid release could be a promising therapeutic strategy to mitigate hepatic lipid accumulation and combat metabolic dysfunction-associated steatotic liver disease, offering a novel approach to addressing this growing health issue.