Biology subjects

Nizhnik, A.

Publications and source records attributed to Nizhnik, A..

4 recordsLinked to original sources

bioRxiv2026

Embryonic TGF-β signaling imposes persistent changes to HSPC clonality and inflammatory landscape

Embryonic hematopoiesis is essential for establishing lifelong blood and immune system function. During development, hematopoietic stem and progenitor cells (HSPCs) acquire intrinsic programs that persist into adulthood and can influence disease susceptibility, yet the molecular signals governing these early-life decisions remain poorly understood. Here, we investigated the role of developmental Transforming Growth Factor-{beta} (TGF-{beta}) signaling in regulating HSPC lineage bias and long-term hematopoietic outcomes. Using the zebrafish model, we found that transient embryonic TGF-{beta} signaling inhibition during the HSPC specification window altered their frequency and migration after emergence from the hemogenic endothelium and movement into the key secondary maturation and expansion niche. Single-cell transcriptomic analysis of embryonic HSPCs revealed repression of migration- and cytoskeleton-associated genes alongside dampened expression of myeloid/macrophage-related genes following ALK5 inhibition. Functionally, early ALK5 blockade reduced macrophage numbers and promoted an M2-like immunosuppressive transcriptional profile. These developmental perturbations produced sustained effects on hematopoietic and immune function into adulthood, including diminished inflammatory gene expression, reduced clonal complexity, and impaired regenerative capacity. Together, our findings identify embryonic TGF-{beta} signaling as a key developmental regulator of HSPC fate and immune programming, with potential implications for immune dysfunction and susceptibility to inflammatory-related disease later in life. PAPER HIGHLIGHTS- Transient developmental signaling perturbations reshape hematopoietic trajectories - Embryogenic TGF-{beta} signaling instructs HSPC lineage priming and macrophage specialization - Early HSPC programming establishes persistent inflammatory states, clonal diversity, and modifies regenerative capacity

developmental biology↗

bioRxiv2025

Hematopoietic Single Cell Atlas Reveals a Diverse Repertoire of Lymphoid Cells in Larval Zebrafish

Embryonic development is a critical time window for the establishment of the hematopoietic and immune systems. During embryogenesis, hematopoietic stem and progenitor cells (HSPCs) that possess divergent differentiation preferences arise and sustain lifelong hematopoiesis. How the pace and differentiation repertoire of native hematopoiesis is set in development and how it evolves as the organism grows is incompletely elucidated. Here, we use temporal lineage tracing of the emerging hematopoietic system during zebrafish development coupled with single cell RNA sequencing to define the origins of larval and adult hematopoietic cells. In both larvae and adult tissues, HSPCs arising earlier during embryogenesis show a predilection for lymphoid lineage production while those arising later are skewed towards erythroid. Moreover, early arising HSPCs are the main contributors to adult tissue resident lymphocytes. Mechanistically, early and late arising HSPCs show divergent transcriptional signatures and differential sensitivities to the levels of the transcription factor Runx1. Additionally, we identified that young larvae possess a more heterogeneous set of lymphoid cells than previously recognized including diverse T-lymphocytes and Innate Lymphoid-like Cells (ILCs). We demonstrated that these newly described larval ILC-like cells reside in lymphoid and mucosal organs and are responsive to viral mimic immune stimulation, indicating their relevance in early vertebrate life. The work provides new fundamental knowledge on how the heterogeneous HSPC pool establishes early immune hierarchies during embryogenesis and its persistence in adulthood.

developmental biology↗

bioRxiv2021

Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis

Hematopoietic stem cells (HSCs) are rare cells that arise in the embryo and sustain adult hematopoiesis. Although the functional potential of nascent HSCs is detectable by transplantation, their native contribution during development is unknown, in part due to the overlapping genesis and marker gene expression with other embryonic blood progenitors. Using single cell transcriptomics, we defined gene signatures that distinguish nascent HSCs from embryonic blood progenitors. Applying a new lineage tracing approach, we selectively tracked HSC output in situ and discovered significantly delayed lymphomyeloid contribution. Using a novel inducible HSC injury model, we demonstrated a negligible impact on larval lymphomyelopoiesis following HSC depletion. HSCs are not merely dormant at this developmental stage as they showed robust regeneration after injury. Combined, our findings illuminate that nascent HSCs self-renew but display differentiation latency, while HSC-independent embryonic progenitors sustain developmental hematopoiesis. Understanding the differences among embryonic HSC and progenitor populations will guide improved de novo generation and expansion of functional HSCs.

developmental biology↗

bioRxiv2019

Firing rate homeostasis occurs in the absence of neuronal activity-regulated transcription

Despite dynamic inputs, neuronal circuits maintain relatively stable firing rates over long periods. This maintenance of firing rate, or firing rate homeostasis, is likely mediated by homeostatic mechanisms such as synaptic scaling and regulation of intrinsic excitability. Because some of these homeostatic mechanisms depend on transcription of activity-regulated genes, including Arc and Homer1a, we hypothesized that activity-regulated transcription would be required for firing rate homeostasis. Surprisingly, however, we found that cultured mouse cortical neurons grown on multi-electrode arrays homeostatically adapt their firing rates to persistent pharmacological stimulation even when activity-regulated transcription is disrupted. Specifically, we observed firing rate homeostasis Arc knock-out neurons, as well as knock-out neurons lacking activity-regulated transcription factors, AP1 and SRF. Firing rate homeostasis also occurred normally during acute pharmacological blockade of transcription. Thus, firing rate homeostasis in response to increased neuronal activity can occur in the absence of neuronal-activity-regulated transcription.\n\nSIGNIFICANCE STATEMENTNeuronal circuits maintain relatively stable firing rates even in the face of dynamic circuit inputs. Understanding the molecular mechanisms that enable this firing rate homeostasis could potentially provide insight into neuronal diseases that present with an imbalance of excitation and inhibition. However, the molecular mechanisms underlying firing rate homeostasis are largely unknown.\n\nIt has long been hypothesized that firing rate homeostasis relies upon neuronal activity-regulated transcription. For example, a 2012 review (PMID 22685679) proposed it, and a 2014 modeling approach established that transcription could theoretically both measure and control firing rate (PMID 24853940). Surprisingly, despite this prediction, we found that cortical neurons undergo firing rate homeostasis in the absence of activity-regulated transcription, indicating that firing rate homeostasis is controlled by non-transcriptional mechanisms.

neuroscience↗