Biology subjects

Gruenschlaeger, F.

Publications and source records attributed to Gruenschlaeger, F..

5 recordsLinked to original sources

bioRxiv2025

A kinetics-based model of hematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells

Residing at the top of the hematopoietic hierarchy, long-term hematopoietic stem cells (HSCs) are capable of self-renewal and sustained blood cell regeneration. Over the past decades, single-cell and clonal analyses have revealed substantial functional and molecular heterogeneity within this compartment, challenging the notion that self-renewal is inherently tied to balanced, multi-lineage blood production. However, a cohesive model that explains the relationships among these diverse HSC states remains elusive. Here, we combined single-cell transplantations of over 1,000 highly purified murine long-term HSCs with in-depth phenotyping of their clonal progeny to achieve a detailed, time-resolved understanding of heterogeneous reconstitution outcomes. We identified reconstitution kinetics as an overall unifying metric of HSC functional potency, with the most potent HSCs displaying the greatest delay in hematopoietic reconstitution. Importantly, a progressive acceleration in reconstitution kinetics was also associated with a gradual shift in mature cell production from platelet and erythro-myeloid bias to balanced, and eventually lymphoid bias. Serial single-cell transplantations of HSCs revealed a unidirectional acceleration in reconstitution kinetics accompanied by a gradual decline in functional potency of daughter HSCs, aligning diverse phenotypes along a linear hierarchical trajectory. Mathematical modeling, together with experimental modulation of lineage-biased blood production, demonstrated that apparent lineage biases actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to occupy the limited compartment sizes of mature lineages. Our study reconciles multiple layers of HSC heterogeneity into a unifying framework, prompting a reevaluation of the meaning of lineage biases in both normal and diseased hematopoiesis, with broad implications for other regenerating tissues during development, homeostasis, and repair.

cell biology↗

bioRxiv2023

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

The long-term consequences of cancer or cancer therapy on the patients immune system years after cancer-free survival remain poorly understood. Here, we have performed an in-depth characterization of the bone marrow ecosystem of multiple myeloma long-term survivors at initial diagnosis and up to 17 years following cancer-free survival. Using comparative single-cell analyses in combination with molecular, genomic and functional approaches, we demonstrate that multiple myeloma long-term survivors display pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently driven by an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible immunological scarring caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of multiple myeloma long-term survivors, revealing reversible and irreversible alterations of the immune compartment, which can serve as diagnostic and predictive tools. Statement of significanceLarge-scale single-cell profiling of a unique cohort of multiple myeloma long-term survivors uncovered that exposure to cancer and its treatment causes both reversible and irreversible immune alterations associated with impaired immunity. These findings have far-reaching implications for the understanding of long-term immune alterations in cancer, which need to be considered also in the context of immune therapeutic approaches. Furthermore, our study demonstrates how cancer-associated immune trafficking can be used to predict disease re-initiation in the bone marrow, opening new avenues for minimally invasive disease monitoring.

cancer biology↗

bioRxiv2023

Single-cell time series analysis reveals the dynamics of in vivo HSPC responses to inflammation

Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing of HSPCs during the sensing, response and recovery phases of the inflammatory response of HSPCs to treatment with the pro-inflammatory cytokine IFN to investigate the HSPCs dynamic changes during acute inflammation. For the analysis of the resulting datasets, we developed a computational pipeline for single-cell time series. Using a semi-supervised response-pseudotime inference approach, we discover a variety of different gene responses of the HSPCs to the treatment. Interestingly, we were able to associate reduced myeloid differentiation programs in HSPCs with reduced myeloid progenitor and differentiated cells following IFN treatment. Altogether, single-cell time series analysis have allowed us to unbiasedly study the heterogeneous and dynamic impact of IFN on the HSPCs.

cell biology↗

bioRxiv2022

The function and decline of the female reproductive tract at single-cell resolution

The female reproductive tract (FRT) undergoes extensive remodeling during each reproductive cycle, regulated by systemic changes in sex hormones. Whether this recurrent remodeling influences a specific organs aging trajectory is unknown. To address this, we systematically characterized at single-cell resolution the morphological and transcriptional changes that occur in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrus cycle, during decidualization, and into aging. Transcriptional and cell-to-cell communication networks in estrus cycle and aging are enriched for ECM reorganization and inflammation, two essential components of FRT remodeling. We directly link the organ-specific level of these two processes over reproductive lifespan with the gradual, age-related development of fibrosis and chronic inflammation. Our data represent a comprehensive atlas of the FRT lifespan, revealing pathological consequences of incomplete resolution of recurrent inflammation and tissue repair.

genomics↗

bioRxiv2019

Combined single-cell and spatial transcriptomics reveals the molecular, cellular and spatial bone marrow niche organization

The bone marrow (BM) constitutes the primary site for life-long blood production and skeletal regeneration. However, its cellular composition and the spatial organization into distinct niches remains controversial. Here, we combine single-cell and spatially resolved transcriptomics to systematically map the molecular and cellular composition of the endosteal, sinusoidal, and arteriolar BM niches. This allowed us to transcriptionally profile all major BM resident cell types, determine their localization, and clarify the cellular and spatial sources of key growth factors and cytokines. Our data demonstrate that previously unrecognized Cxcl12-abundant reticular (CAR) cell subsets (i.e. Adipo- and Osteo-CAR cells) differentially localize to sinusoidal or arteriolar surfaces, locally act as professional cytokine secreting cells, and thereby establish distinct peri-vascular micro-niches. Importantly, we also demonstrate that the 3-dimensional organization of the BM can be accurately inferred from single-cell gene expression data using the newly developed RNA-Magnet algorithm. Together, our study reveals the cellular and spatial organization of BM niches, and offers a novel strategy to dissect the complex organization of whole organs in a systematic manner.\n\nOne Sentence SummaryIntegration of single-cell and spatial transcriptomics reveals the molecular, cellular and spatial organization of bone marrow niches

developmental biology↗