Center for Excellence in Molecular Cell Science

Exosomes serve as intercellular communication vectors and are involved in a broad range of physiological functions. Although exosome-based therapies have demonstrated diverse functional potential, the regulatory mechanisms underlying their biogenesis and secretion remain poorly understood. Here, we report that TEAD1 functions as a molecular switch, dramatically enhancing the synthesis and secretion of exosomes. Mechanistically, TEAD1 enhances exosome secretion by promoting the expression of exosome secretion-associated proteins RAB11, CD9, and SNAP23. We found that TEAD1 enhances exosome secretion from adipose-derived mesenchymal stem cells, thereby promoting skin wound healing in diabetic mice. Similarly, TEAD1 promotes the release of exosomes from bone marrow-derived mesenchymal stem cells, thereby facilitating spinal cord injury (SCI) repair. Our study elucidates a novel role for TEAD1 in driving exosome secretion in different cell types, highlighting the therapeutic potential of TEAD1 in enhancing tissue regeneration, particularly in diabetic wound healing and SCI repair.

During spermatogenesis, the unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI) and form a heterochromatic XY body. Defects in MSCI lead to meiotic arrest and male infertility. Although DNA damage response (DDR) factors are established as key initiators of MSCI, how transcriptional silencing is subsequently achieved remains elusive. Here, we identify the nucleolar components NPM1, SENP3, and rRNA as essential downstream effectors of DDR signaling in MSCI. During pachytene, these components migrate to and transiently cover the XY body during MSCI establishment, before becoming restricted to a corner of the XY body. Genetic deletion of Npm1 or Senp3, or inhibition of rRNA transcription severely impairs MSCI. Mechanistically, SENP3-mediated deSUMOylation of NPM1 promotes its interaction with rRNA, enabling liquid-liquid phase separation, via which they exclude Pol II from the XY body. Together, these data reveal a critical role of nucleolar components in the transcriptional regulation of MSCI in mammalian spermatogenesis.

Somatic hypermutation (SHM) drives antibody affinity maturation in B cells. By mimicking this process, guided hypermutation (GHM) tools employing CRISPR systems and activation-induced cytidine deaminase (AID) have advanced antibody development. However, GHM-induced mutations in cultured cells exhibit mutation patterns distinct from those observed in natural antibody diversification following in vivo affinity selection. To address this, we engineer a hyper-antibody editor, HAE1, by integrating cytidine and adenine deaminases with a nicked, PAMless Cas9 variant, SpRY, to closely resemble the mutation spectrum of natural SHM. Moreover, to streamline mutation, selection, and validation within the same cells, we develop a dual-expression system in HEK293F cells that allows simultaneous expression of both transmembrane and secreted full-length antibodies. Using this system, we apply HAE1 to the SARS-CoV-2 neutralizing antibody CV07-209 and restore the antibody's binding affinity and neutralization potency against Omicron variants, specifically BA.1, including at least one mutation beyond the reach of current GHM tools. HAE1 thus provides a versatile, high-throughput strategy for expediting antibody evolution, presenting significant potential for therapeutic antibody development and protein engineering.

Abstract The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3 , ptpn11 , pi4ka , upf3b , and cul1 , revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 ⁺ pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

Prostate cancer resembles differentiated secretory luminal cells and shows cell-autonomous dependence on androgen receptor (AR) signaling, yet normal luminal cells are often considered dependent on paracrine stromal AR signaling. To resolve this, we conditionally deleted Ar in luminal acinar cells in vivo . Ar -deleted luminal cells persisted short-term, in contrast to the rapid regression observed after castration, but were impaired in regeneration and progressively lost. Their depletion was accompanied by replacement through basal-to-luminal differentiation of AR intact basal cells. Transcriptomic and chromatin profiling showed cell-autonomous suppression of the secretory program with induction of stemness, inflammatory, and epithelial-to-mesenchymal transition signatures after AR loss. Mechanistically, the MAP kinase pathway and downstream AP-1 transcription factors were activated and functionally validated, and MAP kinase inhibition selectively depleted AR-deleted luminal cells, indicating a compensatory survival pathway. These findings define intrinsic roles for luminal AR in maintaining differentiation, restraining plasticity, and sustaining regeneration and homeostatic turnover, providing a mechanistic basis for AR dependence in prostate cancer.

Abstract Electron cyclotron harmonic (ECH) waves, a subset of electron Bernstein modes, are characterized by their distinct harmonic frequency structures. In the outer magnetosphere of the Earth, these waves play a vital role in electron scattering, pitch‐angle diffusion, and the subsequent precipitation of particles into the ionosphere. In contrast, their properties in the vicinity of the Lunar surface remain relatively poorly understood. In this study, we investigate the statistical characteristics of ECH waves using 8 years of observations from the ARTEMIS mission, with the objective of systematically characterizing their behavior across diverse Lunar plasma environments. Our analysis indicates that the overall occurrence rate of ECH waves within the region is approximately 0.099%, but this rate rises to more than 1% on the anti‐sun side in close proximity to the Moon. Moreover, the majority of ECH wave events are detected when the Moon resides within the Earth's magnetotail. On the anti‐sun side, enhanced ECH wave amplitudes are most pronounced in the near Lunar surface region. These results demonstrate that the local Lunar plasma environment strongly influences ECH wave activity, with Lunar magnetic field anomalies significantly modulating the occurrence rate of ECH waves while exerting no substantial influence on their amplitude. Collectively, these findings provide new insights into the plasma processes operating near the Lunar surface.

The Xiatongling tungsten‑molybdenum‑bismuth (W-Mo-Be) deposit, located in the Nanling metallogenic belt, is a stockwork and quartz vein-type W-Mo-Be system developed within and along the contact zone of a medium- to fine-grained granite intrusion. Although previous studies have focused on the magmatic age and geochemical features of the intrusion, and indirectly constrained the mineralization age using molybdenite geochronology, the precise metallogenic chronology, sources of ore-forming materials, and key factors controlling W-Mo-Be mineralization remain poorly understood. This study presents an integrated geochemical and geochronological investigation of zircon, apatite, and wolframite from the deposit to constrain its petrogenesis and mineralization. The zircon U Pb age of the granite (ca. 154 Ma) corresponds to the wolframite U Pb age (ca. 154 Ma), establishing a genetic link between magmatism and tungsten mineralization. Geochemical data indicate that the granite is weakly peraluminous (A/CNK = 1.03 to 1.08), characterized by high SiO₂, U, and Ta, and low Ba, Sr, and Zr + Nb + Ce + Y, typical of highly fractionated S-type granites. Zircon ε Hf (t) values of −7.75 to −10.64 and apatite ε Nd (t) values of −15.56 to −8.97 indicate derivation from the Proterozoic metasedimentary basement of the Wugongshan area, which was characterized by pre-enrichment in W, Mo, and Be. Integrated whole-rock and wolframite geochemical data reveal consistent and pronounced negative Eu anomalies in both wolframite and the Xiatongling granite. Combined with robust geochronological constraints, these findings support the interpretation that the reduced ore-forming fluids were directly exsolved from the reduced, granitic magma. Based on the integrated evidence, we conclude that pre-enrichment of the source and extensive fractional crystallization were key factors for the formation of the Xiatongling W-Mo-Be deposit. • U–Pb ages show a link between Xiatongling mineralization and granitic magmatism. • Ore-forming fluids were directly inherited from the granitic magma. • The magma source originates from the Wugongshan metasedimentary basement. • Source pre-enrichment and fractional crystallization controlled W-Mo-Be deposit formation.

Neointimal hyperplasia (NIH) is a major pathological feature of vascular injury, yet its cellular and molecular drivers remain elusive. Here, using a mouse model of ligation-induced carotid artery NIH, we identify a population of Tenascin C-expressing (Tnc⁺) myofibroblasts (MF). We demonstrate a TNC-driven transition of adventitial fibroblasts (AF) into Tnc⁺ MFs via integrin αvβ1, initiating a positive feedback loop that sustains MF accumulation. In vitro, Tnc⁺ MFs enhance neurite outgrowth, and in vivo, they spatially associate with aberrant axon growth and macrophage accumulation in the perivascular niche. Mechanistically, TNC-activated sensory nerves release CCL2 to recruit macrophages and position them along growing axons. Fibroblast-specific Tnc deletion or sensory neuron inhibition attenuates perivascular hyperinnervation, macrophage recruitment, and neointimal thickening. Importantly, we observe aberrant nerve fibers and macrophage infiltration in human NIH specimens. Thus, we describe a TNC-driven fibroblast-nerve-macrophage axis that sustains inflammation and promotes vascular remodeling. Targeting TNC may offer new therapeutic avenues for vascular diseases.