Biology subjects

Wang, J. S.

Publications and source records attributed to Wang, J. S..

6 recordsLinked to original sources

bioRxiv2026

Supramolecular hydrogel viscoelasticity regulates in situ tertiary lymphoid neogenesis

Tertiary lymphoid structures (TLSs) are organized three-dimensional immune niches associated with improved antitumor immunity, which has galvanized efforts to induce them artificially using biomaterials. However, these strategies have largely focused on soluble cue delivery, leaving the role of scaffold physical properties poorly understood. Here, we developed injectable, liposome-crosslinked supramolecular hydrogels spanning soft and stiff formulations to determine how scaffold mechanical properties regulate in situ tertiary lymphoid neogenesis. The formulations differed in their viscoelastic properties while maintaining broadly comparable release of ovalbumin and LIGHT. Soft hydrogels underwent distributed cellular infiltration and material replacement, transitioning from an early myeloid-rich response to vascularized, lymphoid-dominant tissues containing B-cell-rich aggregates adjacent to T-cell regions, with B-cell organization peaking at day 14. Single-cell RNA sequencing revealed that transient interferon-associated neutrophil and macrophage states in the early niche preceded the emergence of TLS-associated transcriptional programs across lymphoid and myeloid populations. In contrast, stiff hydrogels resisted infiltration and perpetuated a niche dominated by activated myeloid cells with limited lymphoid organization. Prophylactically implanted soft hydrogels improved early melanoma control relative to stiff hydrogels under checkpoint blockade, and a single soft-hydrogel implantation restrained tumor growth even without checkpoint blockade. Together, these findings establish scaffold mechanics and remodeling as active regulators of engineered immune-tissue organization and provide design principles for directing the development of local TLS-like niches.

bioengineering↗

bioRxiv2021

Partial prevention of glucocorticoid-induced osteocyte deterioration with osteocrin gene therapy

Glucocorticoid (GC)-induced osteoporosis and subsequent bone fragility are preceded by death and dysfunction at the cellular level. In particular, short-term glucocorticoid excess suppresses osteocyte remodeling of the surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts homeostatic bone remodeling. Preventing apoptosis and preserving osteocyte morphology and function could be effective means of preventing bone loss during glucocorticoid excess. We hypothesized that osteocrin, which preserves osteocyte viability and morphology in other models where osteocyte defects exist, could prevent osteocyte death and dysfunction in a GC excess model. We used a liver-targeted adeno-associated virus (AAV8) to induce osteocrin overexpression in mice one week prior to implantation with prednisolone or placebo pellets. After 28 days, tissues were collected for micro-CT and histological analysis. GC excess caused the expected reduction in cortical bone thickness and osteocyte canalicular length in control AAV8-treated mice, and these effects were blunted in mice overexpressing osteocrin. However, GC-induced changes in cortical porosity, trabecular bone mass, and gene expression were not prevented by osteocrin. While the mechanism of osteocrins effects on osteocyte morphology warrants further investigation, this study does not support a role for this model of osteocrin supplementation to combat the full skeletal effects of GC excess.

physiology↗

bioRxiv2021

Crustacean cardiac ganglion model reveals constraints on morphology and conductances

The crustacean cardiac ganglion (CG) network coordinates the rhythmic contractions of the heart muscle to control the circulation of blood. The network consists of 9 cells, 5 large motor cells (LC1-5) and 4 small endogenous pacemaker cells (SCs). We report a new three-compartmental biophysical model of an LC that is morphologically realistic and includes provision for inputs from the SCs via a gap-junction coupled spike-initiation-zone (SIZ) compartments. To determine physiologically viable LC models in this realistic configuration, maximal conductances in three compartments of an LC are determined by random sampling from a biologically-characterized 9D-parameter space, followed by a three-stage rejection protocol that checks for conformity with electrophysiological features from single cell traces. LC models that pass the single cell rejection protocol are then incorporated into a network model which is then used in a final rejection protocol stage. Using disparate experimental data, the study provides hitherto unknown structure-function insights related to the crustacean cardiac ganglion large cell, including predictions about morphology including the role of its SIZ, and the differential roles of active conductances in the three compartments. Further, we extend analyses of emergent conductance relationships and correlations in model neurons relative to their biological counterparts, allowing us to make inferences both with respect to the biological system as well as the implications of the ability to detect such relationships in populations of model neurons going forward.

neuroscience↗

bioRxiv2021

A cooperative network at the nuclear envelope counteracts LINC-mediated forces during oogenesis in C. elegans

Oogenesis involves meiosis and oocyte maturation. Both processes rely on mechanical forces (Lee et al., 2015; Nagamatsu et al., 2019; Rog and Dernburg, 2015; Sato et al., 2009; Tsatskis et al., 2020; Wynne et al., 2012), which can be transduced from the cytoskeleton to the nuclear envelope (NE) through linker of nucleoskeleton and cytoskeleton (LINC) complexes (Burke, 2018; Chang et al., 2015; Fan et al., 2020; Link et al., 2014). Gametes must protect their genomes from damage in this mechanically stressful environment. In C. elegans, oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to nuclear collapse. Here we deploy the auxin-inducible degradation system to investigate the balance of forces that drive this collapse and protect oocyte nuclei. We find that nuclear collapse is not a consequence of apoptosis. It is promoted by dynein and a LINC complex comprised of SUN-1 and ZYG-12, which assumes polarized distribution at the NE in response to dynein-mediated forces. We also show that the lamin meshwork works in parallel with other inner nuclear membrane (INM) proteins to counteract mechanical stress at the NE during oogenesis. We speculate that a similar network may protect oocyte integrity during the long arrest period in mammals.

cell biology↗

bioRxiv2021

Meiotic cell cycle progression requires adaptation to a constitutive DNA damage signal

Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in "homolog engagement" is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans, recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break induction. Inactivation of CHK-2 ends double-strand break formation and promotes crossover designation and cell cycle progression. These findings illuminate how meiotic cells ensure crossover formation and accurate chromosome segregation. SummaryAccurate chromosome segregation during meiosis requires crossovers between each pair of homologs. Zhang et al. show that meiotic progression in C. elegans involves inactivation of CHK-2 by PLK-2 in response to synapsis and formation of crossover precursors on all chromosomes.

cell biology↗

bioRxiv2021

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Osteocytes use an elaborate network of dendritic connections to control bone remodeling. Some osteoblasts embed within mineralized bone matrix, change shape, and become osteocytes. The molecular circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites. Unbiased profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues phenotypic and molecular defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates overt defects in osteocyte maturation in vivo in the absence of Sp7. Sp7-dependent gene networks enriched in developing osteocytes are associated with rare and common human skeletal traits. Moreover, humans homozygous for the osteogenesis imperfecta-causing SP7R316C mutation show dramatic defects in osteocyte morphology. Genes that mark osteocytes in vivo and that are regulated by Sp7 in vitro are highly enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. Taken together, these findings reveal a crucial role for Sp7 and its target gene Osteocrin in osteocytogenesis, demonstrating that pathways that control osteocyte development influence human bone diseases.

molecular biology↗