Biology subjects

Mochizuki-Kashio, M.

Publications and source records attributed to Mochizuki-Kashio, M..

3 recordsLinked to original sources

bioRxiv2026

Inflammatory restraint and membrane lipid integrity protect hematopoietic stem cells under stress

Life-long production of blood requires the preservation of hematopoietic stem cell (HSCs) regenerative capacity during inflammation. The cytokine, Thrombopoietin (THPO), is essential for HSC maintenance yet its role during inflammatory stress remains incompletely understood. Long-term repopulating potential was rapidly depleted in THPO-deficient HSCs upon poly(I:C) administration through inflammatory pyroptosis. Transcriptomic and chromatin accessibility analyses revealed constitutive interferon (IFN) pathway activation in THPO-deficient HSCs, characterized by enhanced STAT1 signaling, increased accessibility of STAT and IRF motifs, and elevated expression of IFN-stimulated genes. Lipidomic profiling further identified selective shifts in sphingomyelin (SM) species and enrichment of features associated with increased bilayer rigidity. THPO-deficient HSCs displayed elevated membrane SM incorporation, impaired membrane fluidity and altered membrane ultrastructure. Genetic ablation of Stat1 normalized membrane lipid abnormalities and reduced pyroptotic activation and restored HSC survival and regenerative function under inflammatory stress. Together, these findings identify a STAT1 and SM metabolism as critical THPO downstream to protect HSCs from inflammatory pyroptosis. Our results reveal membrane lipid homeostasis as a fundamental mechanism through which cytokine signaling safeguards HSC function during stress.

cell biology↗

bioRxiv2023

Long-term combination therapy with Metformin and Oxymetholone in a Fanconi Anemia mouse model

Fanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing inactivating mutations in one or more genes in the FA pathway partially mimic the human disease. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow (BM) hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wild-type controls with either MET alone, OXM alone, MET+OXM or placebo diet. Both male and female mice were treated from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=0.01) and hemoglobin levels (p<0.05). In addition, the percentage of quiescent HSC (LSK) was significantly increased (p=0.001) by long-term treatment with MET alone. However, the absolute number of progenitors, measured by LSK frequency or CFU-S, was not significantly altered by MET therapy. The combination of metformin and oxymetholone did not result in a significant synergistic effect on any parameter. Male animals on MET+OXM or MET alone were significantly leaner than controls at 18 months, regardless of genotype. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. Highlights- Long-term coadministration of metformin in combination oxymetholone is well tolerated by Fancd2-/- mice. - HSC quiescence in mutant mice was enhanced by treatment with metformin alone. - Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

genetics↗

bioRxiv2020

FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC

Bone marrow failure (BMF) in Fanconi Anemia (FA) results from exhaustion of hematopoietic stem cells (HSC), but the physiological role of FA proteins in HSC pool integrity remains unknown. Herein we demonstrate that FANCD2, a core component of the FA pathway, counters replication stress during developmental HSC expansion in the fetal liver (FL). Rapid rates of proliferation and FANCD2 deficient result in excess RPA-coated ssDNA, and provoke pChk1 activation and Cdkn1a(p21) nuclear localization in fetal Fancd2-/- HSC. Checkpoint mediated S-phase delays induced by Cdkn1a(p21) are rescued by Tgf-{beta} inhibition, but pChk1 activation is further aggravated. Our observations reveal the mechanism and physiological context by which FANCD2 safeguards HSC pool formation during development.

developmental biology↗