Biology subjects

Swann, J. W.

Publications and source records attributed to Swann, J. W..

8 recordsLinked to original sources

bioRxiv2026

NicheScribe: consistent and generalizable annotation of stromal cells in the murine bone marrow niche

Hematopoietic stem and progenitor cells (HSPC) depend on interactions with nearby stromal cells to support their homeostatic functions and mount responses to perturbations. The murine bone marrow (BM) niche can be profiled using single-cell RNA sequencing (scRNA-seq), but there is considerable inconsistency in cell type identification, and uncertainty over how populations can be isolated prospectively by flow cytometry. Here, we produced new scRNA-seq reference datasets using purified populations of murine BM stromal cells, which we used to create a bespoke classifier for stromal cells. Our NicheScribe approach is consistent, accurate, and generalizable to query datasets irrespective of methods used for cell isolation. Moreover, consistent annotation permits comparative analyses of the same stromal cells across different bone types and perturbations like inflammation, neoplasia, and aging. Our work provides new tools for consistent cell type annotation in the murine BM niche and new insights for combined molecular and functional analyses.

cell biology↗

bioRxiv2025

Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation

Hematopoietic stem and progenitor cells (HSPC) respond to infections, inflammation, and regenerative challenges using a collection of cellular and molecular mechanisms termed emergency myelopoiesis (EM) pathways. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single cell RNA sequencing (scRNA-seq) of HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies to enhance myelopoiesis acting at different levels of the HSPC hierarchy, which are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based module of EM engagement across diverse inflammatory challenges, which informs outcome in adult and pediatric human acute myeloid leukemia. Collectively, our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts. HIGHLIGHTSO_LINew HemaScribe method for hematopoietic progenitor annotation in scRNA-seq datasets C_LIO_LIDifferent emergency myelopoiesis (EM) inducers act at distinct hematopoiesis levels C_LIO_LIUnique and shared transcriptional response modules enacted by different EM inducers C_LIO_LIA myeloid progenitor EM module informs outcome in acute myeloid leukemia C_LI eTOC BLURBSwann et al. conduct comparative analysis of single cell RNA sequencing data from multiple emergency myelopoiesis models, finding that different perturbations act at various levels of the hematopoietic hierarchy and recruit distinct sets of molecular mechanisms to enhance myelopoiesis. In particular, they identify a conserved myeloid progenitor-based activation module across multiple disease conditions, which informs outcome in human acute myeloid leukemia. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/656712v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@ffcd62org.highwire.dtl.DTLVardef@50eaeorg.highwire.dtl.DTLVardef@6df44org.highwire.dtl.DTLVardef@12bfacf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

New Insights into Epileptic Spasm Generation and Treatment from the TTX Animal Model

Currently, we have an incomplete understanding of the mechanisms underlying infantile epileptic spasms syndrome (IESS). However, over the past decade, significant efforts have been made to develop IESS animal models to provide much-needed mechanistic information for therapy development. Our laboratory has focused on the TTX model, in which tetrodotoxin (TTX) is infused into the neocortex of infant rats, producing a lesion at the infusion site and mimicking IESS resulting from acquired structural brain abnormalities. Subsequent electrophysiological studies showed that the epileptic spasms originate from neocortical layer V pyramidal cells. Importantly, experimental maneuvers that increase the excitability of these cells produce focal seizures in non-epileptic control animals but never produce them in TTX-infused epileptic rats; instead, epileptic spasms are produced in epileptic rats, indicating a significant transformation in the operations of neocortical networks. At the molecular level, studies showed that the expression of insulin-like growth factor 1 was markedly reduced in the cortex and this corresponded with a loss of presynaptic GABAergic nerve terminals. Very similar observations were made in surgically resected tissue from IESS patients with a history of perinatal strokes. Other experiments in conditional knockout mice indicated that IGF-1 plays a critical role in the maturation of neocortical inhibitory connectivity. This finding led to our hypothesis that the loss of IGF-1 in epileptic animals impairs inhibitory interneuron synaptogenesis and is responsible for spasms. To test this idea, we treated epileptic rats with the IGF-1-derived tripeptide (1-3)IGF-1, which was shown to act through IGF-1s receptor. (1-3)IGF-1 rescued inhibitory interneuron connectivity, restored IGF-1 levels, and abolished spasms. Thus (1-3)IGF-1 or its analogues are potential novel treatments for IESS following perinatal brain injury. We conclude by discussing our findings in the broader context of the often-debated final common pathway hypothesis for IESS. We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Plain Language SummaryWe review recent findings from the TTX animal model of infantile epileptic spasms syndrome, which show that these seizures come from an area of the brain called the neocortex. In this area, the amount of an important growth factor called IGF-1 is reduced, as is the number of inhibitory synapses that play an important role in preventing seizures. Other results indicate that the loss of IGF-1 prevents the normal development of these inhibitory synapses. Treatment of epileptic animals with (1-3)IGF-1 restored IGF-1 levels and inhibitory synapses and abolished spasms. Thus, (1-3)IGF-1 or an analogue are potential new therapies for epileptic spasms.

neuroscience↗

bioRxiv2024

IGF-1 IMPACTS NEOCORTICAL INTERNEURON CONNECTIVITY IN EPILEPTIC SPASM GENERATION AND RESOLUTION

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1-3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1-3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1-3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder.

neuroscience↗

bioRxiv2024

Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche

Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.

cell biology↗

bioRxiv2023

Maternal IL-10 restricts fetal emergency myelopoiesis

Neonates, in contrast to adults, are highly susceptible to inflammation and infection. Here we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPC) respond to inflammation, testing the hypothesis that deficits in engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that despite similar molecular wiring as adults, fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical EM transcriptional program. Moreover, we find that fetal HSPCs are capable of responding to EM-inducing inflammatory stimuli in vitro, but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero. Accordingly, we demonstrate that loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of premature parturition. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection. HIGHLIGHTSO_LIThe structure of the HSPC compartment is conserved from late fetal to adult life. C_LIO_LIFetal HSPCs have diminished steady-state myeloid cell production compared to adult. C_LIO_LIFetal HSPCs are restricted from engaging in emergency myelopoiesis by maternal IL-10. C_LIO_LIRestriction of emergency myelopoiesis may explain neutropenia in septic neonates. C_LI eTOC BLURBFetal hematopoietic stem and progenitor cells are restricted from activating emergency myelopoiesis pathways by maternal IL-10, resulting in inadequate myeloid cell production in response to inflammatory challenges and contributing to neonatal neutropenia.

developmental biology↗

bioRxiv2023

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells

Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction (1). Autophagy is central for the benefits associated with activation of longevity signaling programs (2), and for HSC function and response to nutrient stress (3,4). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional (4). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche (5). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity. One-Sentence SummaryAutophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.

cell biology↗

bioRxiv2019

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, but the underlying pathogeneses are poorly understood. Syntaxin-binding protein 1 (STXBP1) is an essential component of the neurotransmitter release machinery. Its de novo heterozygous mutations are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, affect a broad spectrum of neurological and neuropsychiatric features common among neurodevelopmental disorders. To gain insight into STXBP1 encephalopathy pathogenesis, we generated new Stxbp1 null alleles in mice and found that Stxbp1 haploinsufficiency impaired cognitive, psychiatric, and motor functions and caused cortical hyperexcitability and seizures. Surprisingly, Stxbp1 haploinsufficiency reduced neurotransmission from cortical parvalbumin- and somatostatin-expressing GABAergic interneurons by differentially decreasing the synaptic strength and connectivity, respectively. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate key features of STXBP1 encephalopathy and indicate that inhibitory dysfunction is likely a key contributor to the disease pathogenesis.

neuroscience↗