Biology subjects

Cornils, K.

Publications and source records attributed to Cornils, K..

4 recordsLinked to original sources

bioRxiv2022

Multimodal Mapping of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Cell-Intrinsic versus Flt3L-Dependent Regulation

The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map that extends the current view of lymphoid development. Our results demonstrate that lymphoid specification follows independent direct or stepwise differentiation pathways converging toward the emergence of CD117lo multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127- (T/NK/ILC) or CD127+ (B) lymphoid pathways. While the emergence of CD127- early lymphoid progenitors is driven by Flt3 signaling, differentiation of their CD127+ counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their precursors. Single-cell mapping of lymphoid differentiation trajectories reveals that a dissociation between proliferation and differentiation phases allows amplification of the precursor pools prior to the onset of antigen receptor rearrangement. Besides demonstrating that B and T/NK/ILC lineages are subjected to differential cell-autonomous versus Flt3-inducible regulation, our results go a long way to reconciling human and mouse models of lymphoid architecture.

immunology↗

bioRxiv2020

Age-independent influence of hematopoietic stem and progenitor cell populations during hematopoietic reconstitution

Hematopoietic stem cell transplantation (HSCT) following myeloablative conditioning represents the only curative treatment option to overcome numerous hematologic malignancies. Despite the overall clinical success to achieve reconstitution of the blood system in many patients, the length of the aplastic phase until recovery response remains a critical parameter for patient survival. Fatal infections are the major risk factor for immunocompromised individuals and in many cases lead to transplant related morbidity and mortality. Therefore, we hypothesized that transplants from young donors might be beneficial for the spatiotemporal blood reconstitution in comparison to old grafts. Here we report on our multicolor-coded barcode system (BC32) to track hematopoietic stem and progenitor cell (HSPC) populations in a murine model of HSCT. By using different experimental settings of young and aged donor and recipient animals we compared the influence of age on graft composition, leukocyte recovery and more precisely, the contribution of individual HSPC subpopulations to the process. We show that blood reconstitution is substantially driven and maintained by HSCs and MPPs, while the latter accounted for higher output rates than HSCs, confirmed by FACS and NGS analyses. Reconstitution patterns were highly polyclonal and stable in all animals aside from variability between individual animals. This leads to the conclusion that HSPCs home, engraft and differentiate independently of donor and recipient age in our experimental conditions. Our findings add to ongoing efforts to expand the application of HSCT in older individuals while minimizing therapy related risks resulting from intensive myeloablative conditioning or incomplete blood reconstitution.

cell biology↗

bioRxiv2019

genBaRcode - a comprehensive R package for genetic barcode analysis

MotivationGenetic barcodes have been established as an efficient method to trace clonal progeny of uniquely labeled cells by introducing artificial genetic sequences into the corresponding genomes. The assessment of those sequences, relies on next generation sequencing and the subsequent analysis aiming to identify sequences of interest and correctly quantifying their abundance.\n\nResultsWe developed the genBaRcode package as a toolbox combining the flexibility of digesting next generation sequencing reads with or without a sophisticated barcode structure, with a variety of error correction approaches and the availability of several types of visualization routines. Furthermore, a graphical user interface was incorporated to allow also less experienced R users package-based analyses. Finally, the provided tool is intended to bridge the gap between generating and analyzing barcode data and thereby supporting the establishment of standardized and reproducible analysis strategies.\n\nAvailabilityThe genBaRcode package is available at CRAN (https://cran.r-project.org/pack-age=genBaRcode).\n\nContactlars.thielecke@tu-dresden.de

bioinformatics↗

bioRxiv2018

Engrafted parenchymal brain macrophages differ from host microglia in transcriptome, epigenome and responsiveness to challenge

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial cells by constantly probing their surroundings with dynamic extensions. Following different conditioning paradigms and bone marrow (BM) / hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that these cells acquire over time microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even following prolonged CNS residence, transcriptomes and epigenomes of engrafted HSC-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, BM graft-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. Also in human HSC transplant recipients, engrafted cells remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for patients treated by HSC gene therapy.

immunology↗