Biology subjects

Aurich, T.

Publications and source records attributed to Aurich, T..

3 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↗

bioRxiv2024

Homogeneously crosslinked in situ hydrogel enclosing high-density human-cancer cells promotes vascularized in vivo tumor modeling for immune cell therapy

Cancer models in animal studies play a central role in cancer research, particularly in investigating vascularized tumor tissues for the validation of immune cell therapies. However, xenografts relying solely on cancer cells are ineffective for optimal tumor tissue formation. Additionally, tumor modeling using hydrogels with cancer cells to promote vascularization often leaves behind residual biomaterials that inhibit integration with surrounding tissues. To address these issues, we utilized a straightforward in vivo vascularized tumor modeling method with a completely degradable, crosslinker-free carboxymethyl chitosan (CMCTS)/oxidized hyaluronic acid (OHA) hydrogel that encapsulates high-density human cancer cells for in situ injection. The CMCTS/oHA hydrogel was fully degraded within 3 weeks, enabling three-dimensional (3D) cell condensation in vitro. 2 weeks after subcutaneous injection in mice, solid tumors formed, with native host vasculature infiltrating the transplanted human cancer cells, confirming spontaneous hydrogel degradation. Following this, human macrophages were administered via tail vein injection, enhancing the accumulation of mouse immune cells in the humanized tumor twofold and showing murine macrophages adjacent to the vasculature. This study thus provides proof-of-concept for a facile and fully vascularized humanized tumor model in mice for validating immune cell therapies. HIGHLIGHTSO_LIThe oHA was prepared using sodium periodate treatment, which facilitated the formation of in situ CMCTS/oHA hydrogels C_LIO_LICMCTS/oHA hydrogels completely degraded within a short period, allowing for 3D cell condensation C_LIO_LIHigh-density cell-laden CMCTS/oHA hydrogels were injected subcutaneously in mice, resulting in the generation of a vascularized solid tumor C_LIO_LIThe transplanted therapeutic cell was observed to adhere to the tumor tissue through the bloodstream C_LI

bioengineering↗

bioRxiv2022

Dynamic DNA methylation reveals novel cis-regulatory elements in murine hematopoiesis

BackgroundThe differentiation of hematopoietic stem and progenitor cells (HSPCs) to terminally differentiated immune cells is accompanied by large-scale remodeling of the DNA methylation landscape. While significant insights into the molecular mechanisms of hematopoietic tissue regeneration were derived from mouse models, profiling of DNA methylation changes has been hampered by high cost or low resolution using the methods available. This problem has been overcome by the recent development of the Infinium Mouse Methylation BeadChip (MMBC) array, facilitating methylation profiling of the mouse genome at single CpG resolution at affordable cost. ResultsWe extended the RnBeads package to provide a computational framework for the analysis of MMBC data. This framework was applied to a newly generated MMBC reference map of mouse hematopoiesis encompassing nine different cell types. The analysis of dynamically regulated CpG sites showed progressive and unidirectional DNA methylation changes from HSPCs to differentiated hematopoietic cells and allowed the identification of lineage- and cell type-specific DNA methylation programs. Comparison to previously published catalogues of cis-regulatory elements (CREs) revealed 12,856 novel putative CREs which were dynamically regulated by DNA methylation (mdCREs). These mdCREs were predominantly associated with patterns of cell type-specific DNA hypomethylation and could be identified as epigenetic control regions regulating the expression of key hematopoietic genes during differentiation. ConclusionsWe established a publicly available analysis pipeline for MMBC datasets and provide a DNA methylation atlas of mouse hematopoiesis. This resource allowed us to identify novel putative CREs involved in hematopoiesis and will serve as a platform to study epigenetic regulation of normal and malignant hematopoiesis.

genomics↗