Biology subjects

Goodhardt, M.

Publications and source records attributed to Goodhardt, M..

5 recordsLinked to original sources

bioRxiv2026

Non-Canonical Heme Oxygenase-1 Function in Hematopoietic Stem Cell Homeostasis and Aging

Heme oxygenase-1 (HO-1, encoded by Hmox1) is a cytoprotective enzyme with well-established roles in defending against oxidative stress. Global Hmox1 deficiency in mice accelerates hematopoietic stem cell (HSC) exhaustion and aging, effects previously attributed primarily to loss of HO-1 activity within the bone marrow (BM) niche. However, the cell-intrinsic contribution of HO-1 to HSC regulation has remained unclear. Here, we show that global Hmox1 deficiency results in accumulation of an expanded but largely quiescent HSC pool characterized by compromised genome maintenance, altered apoptotic signaling, and defective cell-cycle checkpoint control. We further demonstrate that HO-1 protein is expressed in HSCs and exhibits a predominantly nuclear, non-canonical localization. Using Hoxb5-CreERT2-mediated conditional deletion of Hmox1 in HSCs, we uncover an intrinsic requirement for HO-1 in controlling early hematopoietic differentiation. HSC-specific loss of HO-1 skews stem cell output toward short-term progenitors and increases colony-forming capacity. Transcriptomic profiling of Hmox1fl/fl;Hoxb5-CreERT2 HSCs revealed broad dysregulation of pathways involved in translation and RNA metabolism, together with aberrant expression of key transcription factors controlling hematopoietic differentiation. Collectively, these findings identify a non-canonical, cell-intrinsic role for HO-1 in regulating HSC homeostasis, differentiation, and aging.

cell biology↗

bioRxiv2023

Altered X-chromosome inactivation predisposes to autoimmune manifestations in mice

In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism that ensures the silencing of one X in females, may participate in these sex-biases. Here, we perturbed the expression of the trigger of XCI, the non-coding RNA Xist, in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signalling pathway, in monocyte/macrophages, dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal centre B cells and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signalling is dysregulated in macrophages, which leads to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity. TeaserThe reason why autoimmunity mostly affects women is unclear. Here, we show that aberrant expression of genes on the X induces signs of lupus in female mice.

immunology↗

bioRxiv2022

Distinct Subsets of Multi-Lymphoid Progenitors Support Ontogeny-Related Changes in Human Lymphopoiesis

Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127-/+ early lymphoid progenitors (ELP). Our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ ELPs which persists until puberty. A further developmental transition is observed in elderly individuals where B-cell differentiation bypasses the CD127+ compartment and branches directly from CD10+ MLPs. Functional analyses indicate that these changes are determined at the level of the hematopoietic stem cell. Besides reconciling controversies about the identity and function of human MLPs, these results may shed light on the causes of age-related differences in the incidence of lymphoblastic leukemia.

immunology↗

bioRxiv2022

Multimodal Mapping of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Cell-Intrinsic versus Flt3L-Dependent Regulation

The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map that extends the current view of lymphoid development. Our results demonstrate that lymphoid specification follows independent direct or stepwise differentiation pathways converging toward the emergence of CD117lo multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127- (T/NK/ILC) or CD127+ (B) lymphoid pathways. While the emergence of CD127- early lymphoid progenitors is driven by Flt3 signaling, differentiation of their CD127+ counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their precursors. Single-cell mapping of lymphoid differentiation trajectories reveals that a dissociation between proliferation and differentiation phases allows amplification of the precursor pools prior to the onset of antigen receptor rearrangement. Besides demonstrating that B and T/NK/ILC lineages are subjected to differential cell-autonomous versus Flt3-inducible regulation, our results go a long way to reconciling human and mouse models of lymphoid architecture.

immunology↗

bioRxiv2019

Reduced RNA turnover as a driver of cellular senescence

Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. While cytoplasmic DNA was shown to drive the inflammatory phenotype of senescent cells, an equivalent role for RNA has never been explored. Here, we show that some senescent cells accumulate long promoter RNAs and 3 gene extensions, rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in detecting double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is correlated with signs of reduced RNA turn-over, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, engineered inactivation of RNA exosome subunit Exosc3 induces expression of multiple senescence markers. A senescence-like RNA accumulation is also observed in cells exposed to oxidative stress, an important trigger of cellular senescence. Altogether, we propose that in a subset of senescent cells, repeat-containing transcripts stabilized by oxidative stress or reduced RNA exosome activity participate, possibly in combination with cytoplasmic DNA, in driving and maintaining the permanent inflammatory state characterizing cellular senescence.

molecular biology↗