Biology subjects

Rauner, M.

Publications and source records attributed to Rauner, M..

6 recordsLinked to original sources

bioRxiv2026

Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.

The regulation of human hematopoietic stem cell (HSC) function within its native bone marrow microenvironment remains poorly understood due to the limitations of existing humanized models. Here, we present a non-conditioned human HSC xenotransplantation platform that serves as a physiologically relevant in vivo surrogate to study these complex cellular interactions. Using this system, we uncover a dynamic, cross-species communication between human HSCs and the murine niche, revealing a profound cellular and molecular plasticity of the bone marrow microenvironment in response to humanization. Upon engraftment, platelet-derived growth factor receptor alpha positive (Pdgfra+) mesenchymal stromal cells (MSCs) undergo significant numerical expansion and a major transcriptional shift, transitioning from a mixed adipo- and osteo-primed state toward a leptin receptor positive (Lepr+) predominantly adipo-primed, hematopoiesis-supporting signature. Functional validation demonstrates that this niche plasticity is a critical determinant of stem cell engraftment: the targeted depletion of Lepr+ MSCs or the genetic deletion of stem cell factor results in the rapid mobilization and lack of engraftment of human HSCs, respectively. Our findings establish niche plasticity as a primary regulator of human HSC function and demonstrate the utility of this cross-species platform as a modular genetic toolbox for precise in vivo engineering of the bone marrow microenvironment. Ultimately, this adaptable system provides a powerful framework for elucidating human stem cell biology and advancing bone marrow transplantation therapies.

cell biology↗

bioRxiv2025

Preclinical Efficacy of Tasquinimod in Myelodysplastic Neoplasms: Restoring Erythropoiesis and Mitigating Bone Loss

Myelodysplastic neoplasms (MDS) are clonal disorders characterized by ineffective hematopoiesis, dysplasia, and a risk of transformation into acute myeloid leukemia. MDS is also associated with a higher incidence of osteoporosis, suggesting a complex interplay between hematopoiesis, the bone marrow (BM) microenvironment, and bone homeostasis. Targeting inflammation has emerged as a promising therapeutic strategy, particularly in lower-risk MDS. Tasquinimod (TASQ) is a small-molecule inhibitor of the inflammatory alarmin S100A9, blocking its interaction with TLR4 and RAGE receptors. We investigated the efficacy of TASQ in modulating inflammation and improving disease phenotype using in vitro and in vivo MDS models. Immunofluorescence staining of human BM identified neutrophils and macrophages as primary S100A9 sources. Exposure of mesenchymal stromal cells (MSCs) to S100A9 induced TLR4 downstream signaling, resulting in increased expression of IRAK1, NF-{kappa}B-p65, IL-1{beta}, IL-18, caspase 1 and PD-L1. These effects were effectively abolished by TASQ. Additionally, TASQ restored the disturbed MSC-mediated hematopoietic support, as demonstrated by increased numbers of cobblestone area-forming cells and colony-forming units. In NHD13 MDS mice, TASQ (30 mg/kg, 12 weeks) improved hemoglobin and red blood cell counts, but exerted no effect in wild-type (WT) mice. Additionally, TASQ improved bone microarchitecture by increasing trabecular number and bone volume, likely a result of reduced osteoclast activity. Our findings suggest that TASQ mitigates inflammasome activation in the MDS BM, improving erythropoiesis and bone health. These results provide a necessary preclinical basis for clinical trials in lower-risk MDS patients, in whom anemia and osteoporosis often coexist.

cell biology↗

bioRxiv2025

Hypoxia Inducible Factor 1α-driven steroidogenesis impacts systemic hematopoiesis

Glucocorticoids regulate hematopoiesis, but how chronic elevation of endogenous glucocorticoid production affects hematopoietic stem cell (HSC) function and immune cell development remains incompletely understood. Using an adrenocortical cell-specific HIF1 (Hypoxia inducible Factor-1)-deficient mouse model (P2H1Ad.Cortex) resulting in elevated glucocorticoid (GC) levels, we here demonstrate that sustained GC exposure promotes hematopoietic stem and progenitor cell (HSPC) expansion while shifting HSCs toward a more quiescent and metabolically restrained state. Functionally, these HSCs exhibited enhanced regenerative potential, as evidenced by superior donor chimerism in transplantation assays. In addition, we observed a striking increase in myeloid progenitors, as well as in their progeny (monocytes and granulocytes). Conversely, B-cell differentiation in the bone marrow was severely impaired, with a strong block at the pre-pro-B cell stage. To determine whether these phenotypes were driven by glucocorticoid receptor (GR) signaling, we performed transplantation experiments using GR-deficient or WT control bone marrow into P2H1Ad.Cortex or WT littermate recipients. This approach decisively demonstrated that both the increase in myeloid cells and the block in B-cell differentiation were GR-dependent, confirming that GC-GR signaling plays a pivotal role in shaping hematopoiesis. Taken together, our findings clearly suggest a direct role for chronic glucocorticoid exposure in regulating HSC function, lineage differentiation, and stress hematopoiesis. The mouse model of adrenocortical cell-specific HIF1 deficiency provides a valuable tool to study the long-term effects of elevated glucocorticoid levels on hematopoietic regulation and may provide further insight into hematologic disorders associated with chronic therapeutic glucocorticoid administration. Article Summary- Our study aimed to elucidate how chronic elevation of glucocorticoids impacts hematopoietic stem cell function and immune cell development using an adrenocortical cell-specific HIF1-deficient mouse model. - The main conclusion is that sustained glucocorticoid exposure, through glucocorticoid receptor signaling, promotes hematopoietic stem and progenitor cell expansion with enhanced regenerative potential while skewing lineage differentiation toward myeloid expansion and impeding B-cell development.

immunology↗

bioRxiv2024

TMPRSS6 cleaves KCNE1 and causes arrhythmias in iron overload disease

Iron storage disease is associated with cardiovascular manifestations, including various forms of cardiac arrhythmias of unknown origin. In this study, cardiac arrhythmias associated with iron overload were investigated in human iPSC-derived cardiomyocytes (hiPSC-CM) and hiPSC-derived sinus node-like pacemaker cells. Among other effects, iron overload leads to an increase in the plasma membrane-anchored protease TMPRSS6. TMPRSS6 cleaves the auxiliary subunit KCNE1 N-terminally and thus modulates the function of both the IKs (KCNQ1/KCNE1 current) and the If (HCN4/KCNE1) ion channels. Furthermore, TMPRSS6 induces a reduction of electric field potential (EFP) count and increased duration in hiPSC-derived ventricular-like cells and in hiPSC-derived pacemaker-like cells. In accordance with these in vitro generated results, TMPRSS6-mediated interactions show pro-arrhythmic effects in silico. Therefore, the TMPRSS6 - KCNE1-KCNQ1 and TMPRSS6 - KCNE1-HCN4 cascades may represent new clinically relevant pro-arrhythmic mechanisms in iron overload diseases.

physiology↗

bioRxiv2024

Endoglin regulates the integrity of the bone marrow vasculature

Endoglin (Eng) is an accessory receptor for transforming growth factor-{beta} (TGF-{beta}) that is critical for maintaining vascular integrity. Mutations in Eng cause hereditary hemorrhagic telangiectasia (HHT), resulting in arteriovenous malformations (AVMs) and blood abnormalities. Despite the known association between Eng deficiency and AVMs, the underlying mechanisms are unclear. In addition, the role of the bone marrow (BM), a major source of immune and blood cells, in endothelial Eng (EC-Eng) deficiency is unexplored. We show that BM blood vessels conditionally deficient in Eng (cKO) undergo a structured remodeling process over four weeks, with distinct proliferative and resolution phases. These phases involve angiogenic set points, the involvement of integrins, and the modulation of vascular integrity. In addition, we observe changes in hematopoietic stem and progenitor cells (HSPC) and circulating granulocytes, along with reduced red blood cells and platelets due to splenic sequestration. Using a conditional heterozygous EC-Eng deficient mouse model, reflecting the genetics of HHT patients, we identify vascular changes similar to those in the cKO model. Taken together, using multiple in vivo approaches, we suggest that reduced Eng expression in the endothelium drives significant BM vascular remodeling, sharing mechanisms with early vascular processes associated with AVM formation. Explanation of NoveltyOur findings reveal that BM blood vessels deficient in endoglin undergo an orchestrated remodeling process with distinct proliferative and resolution phases over several weeks. We identify specific angiogenic set points and profound alterations in vascular integrity, along with hematopoietic changes starting at the level of hematopoietic stem and progenitor cells. These findings advance our understanding of the role of Eng in vascular remodeling and may provide novel therapeutic targets for HHT. Key PointsO_LIConditional EC-Eng deficiency leads to vascular remodeling in the BM of mice in a temporally orchestrated manner. C_LIO_LIEC-Eng facilitates vascular integrity, hematopoietic homeostasis, and immune cell mobilization. C_LI

molecular biology↗

bioRxiv2021

Post-embryonic development and aging of the appendicular skeleton in Ambystoma mexicanum

BackgroundThe axolotl is a key model to study appendicular regeneration. The limb complexity resembles that of humans in structure and tissue components; however, axolotl limbs develop post-embryonically. In this work, we evaluated the post-embryonic development of the appendicular skeleton and its changes with aging. ResultsThe juvenile limb skeleton is formed mostly by Sox9/Col1a2 cartilage cells. Ossification of the appendicular skeleton starts when animals reach a length of 10 cm, and cartilage cells are replaced by a primary ossification center, consisting of cortical bone and an adipocyte-filled marrow cavity. Vascularization is associated with the ossification center and the marrow cavity formation. We identified the contribution of Col1a2-descendants to bone and adipocytes. Moreover, ossification progresses with age towards the epiphyses of long bones. Axolotls are neotenic salamanders, and still ossification remains responsive to L-thyroxine, increasing the rate of bone formation. ConclusionsIn axolotls, bone maturation is a continuous process that extends throughout their life. Ossification of the appendicular bones is slow and continues until the complete element is ossified. The cellular components of the appendicular skeleton change accordingly during ossification, creating a heterogenous landscape in each element. The continuous maturation of the bone is accompanied by a continuous body growth.

developmental biology↗