Biology subjects

Sedlmeier, A.

Publications and source records attributed to Sedlmeier, A..

2 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↗