Transient developmental signaling perturbations reshape hematopoietic trajectories produce sustained effects on hematopoietic and immune function into adulthood, including diminished inflammatory gene expression, reduced clonal complexity, and impaired regenerative capacity.
Abstract
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-β (TGF-β) signaling in regulating HSPC lineage bias and long-term hematopoietic outcomes. Using the zebrafish model, we found that transient embryonic TGF-β 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-β 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-β signaling instructs HSPC lineage priming and macrophage specialization – Early HSPC programming establishes persistent inflammatory states, clonal diversity, and modifies regenerative capacity
Using mice carrying a mutation in the CBFβ2 isoform, it is demonstrated that CBFβ2 haploinsufficiency rewires transcriptional regulatory circuits in adult bone marrow progenitors, rendering them permissive for an early life-restricted Tγδ17 cells.
Michela Frascoli, Alyssa Berthelette, Joonsoo Kang et al.· Journal of Immunology· 0 citations
Gfi1 dynamics define EHT onset and functionally distinct HSC stemness, and a subset of adult bone marrow HSCs retained expression and exhibited superior repopulating and self-renewal capacity.
It is reported that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice, establishing PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.
Qi-Wen Dong, Wei-Wei Xiao, Junsong Huang et al.· Journal of genetics and geno...· 0 citations
Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong blood production, yet the molecular mechanisms underlying their functional decline with age remain incompletely understood. Understanding how aging alters the transcriptomic landscape of HSPCs is critical to uncovering the origins of immune system aging. We performed a comprehensive single‐cell RNA sequencing analysis integrating over 300,000 bone marrow‐derived HSPCs from 50 healthy individuals spanning 19 to 84 years of age. Aging was associated with immune lineage skewing, marked by increased myeloid and decreased lymphoid output in both bone marrow and peripheral blood. Subtle increases in HSCs, MEPs, and myeloid progenitors alongside reductions in lymphoid progenitors were already evident in aged bone marrow, suggesting that lineage bias is encoded at the progenitor level. Age‐associated transcriptional changes included extensive upregulation of ribosomal genes encoding small (RPS11, RPS12, RPS23) and large (RPL9, RPL19, RPL24) cytoplasmic ribosomal subunit proteins, as well as pro‐inflammatory mediators (IL1B, IL18, TGFB1, S100A8). Enrichment analysis identified mitochondrial function, ribosome biogenesis, chromatin remodeling, and inflammatory signaling as key ontologies disrupted during HSPC aging. Our study identifies molecular signatures of systemic aging rooted in bone marrow HSPCs and suggests that dysregulated ribosomal protein gene expression is an under‐appreciated hallmark of hematopoietic stem cell aging.
Roger Atanga, Saurav Mallik, Soumita Seth et al.· Advances in Biology· 0 citations
Microglia, embryonically derived tissue-resident macrophages of the central nervous system, are essential for brain development, homeostasis, and disease. Although transforming growth factor β (TGF-β) signaling is required for mammalian microglia ontogeny, its precise role and evolutionary conservation remain unclear. Using zebrafish as a vertebrate in vivo model, we find Tgf-β receptor signaling as a conserved, cell-intrinsic regulator of microglial differentiation. Pharmacological or genetic disruption of Tgf-β receptor function arrests microglial development after progenitor migration to the embryonic neuroepithelium, preventing activation of the microglial gene expression program. Genetic rescue experiments demonstrate a direct requirement for Tgf-β receptor signaling within the myeloid lineage. We identify Tgf-β1 as the key ligand driving this process and show that sustained signaling is required to maintain microglial identity. Adult zebrafish microglia, whose origin differs from that in mice, similarly fail to differentiate without Tgf-β signaling. Together, these findings establish an evolutionarily conserved TGF-β signaling axis that instructs and maintains microglial identity in vivo.
M. Miserocchi, Pauline De Meyer, Ruben Lattuca et al.· Cell Reports· 0 citations
Chronic inflammatory diseases often originate in local tissues yet display systemic immune abnormalities, suggesting durable changes in upstream immune regulation. Crohn’s disease (CD), while centered in the intestine, is a systemic inflammatory disorder. Hematopoietic stem and progenitor cells (HSPCs) can retain memory of inflammatory cues, leading to sustained changes in hematopoiesis and immune responsiveness. Here, we investigated how chronic intestinal inflammation in CD reprograms HSPCs and contributes to disease.
We analyzed a longitudinal CD cohort using paired pre- and post—anti-TNF blood samples with healthy controls. Circulating HSPCs and mature immune cells were profiled by single-nucleus RNA-seq and ATAC-seq with progenitor enrichment, enabling integrated multiomic and gene regulatory analyses. Functional relevance was assessed using bulk RNA-seq and ATAC-seq of HSPCs from a murine DSS colitis model, together with bone marrow chimera and transplantation experiments.
HSPCs from individuals with CD exhibited loss of quiescence, metabolic activation, epigenetic priming of inflammatory and stress-responsive programs, and shifts in progenitor composition. These molecular programs were conserved in murine colitis HSPCs, with altered progenitor subtype frequencies and pathogenic hematopoiesis, as inflammation-experienced HSPCs exacerbated disease upon transplantation. Circulating monocytes in CD also shifted toward inflammatory subpopulations sharing transcriptional and regulatory features with reprogrammed HSPCs. A central TNF—NF-κB regulatory axis underpinned these alterations, and anti-TNF therapy largely normalized HSPC composition, metabolic state, and inflammatory gene regulatory networks.
Inflammatory hematopoiesis represents a durable, therapy-responsive driver of CD. HSPCs act as a systemic reservoir of inflammatory memory, while TNF blockade partially restores hematopoietic homeostasis, highlighting progenitor reprogramming as a therapeutic target.
NA
Hematopoiesis and Immune System Development (HEM)
Jin-Gyu Cheong, Chenyang Jiang, Muxue Du et al.· Journal of Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
