Biology subjects

Klein Geltink, R. I.

Publications and source records attributed to Klein Geltink, R. I..

5 recordsLinked to original sources

bioRxiv2026

Mitochondrial transfer mediates metabolic communication between beta cells and islet macrophages

Pancreatic islet macrophages support islet homeostasis and adapt their metabolic program in response to environmental cues, including beta cell released factors. Intercellular mitochondrial transfer is a biological process that modulates cellular responses. To test whether beta cells, which are strongly secretory, transfer mitochondria to islet macrophages, we generated mice with beta cell-specific expression of mitochondrial GFP (PhAMfloxIns1Cre). We demonstrate that beta cells transfer mitochondria to islet macrophages in vivo and in vitro. Diabetogenic stressors did not alter the frequency of mitochondrial transfer and macrophages containing beta cell-derived GFP exhibit increased protein synthesis rates. RNA-seq identified upregulation of activity-regulated cytoskeleton associated protein (Arc) in macrophages receiving beta cell-derived mitochondria, while disruption of actin cytoskeleton dynamics prevented mitochondrial transfer. Together, these findings identify mitochondrial transfer as a previously unrecognized mechanism of beta cell-macrophage communication that may contribute to islet homeostasis and immune regulation.

cell biology↗

bioRxiv2025

Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy

Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. We applied an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) had increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.

immunology↗

bioRxiv2025

Biosynthetic plasticity enables CD8+ T cell functional resilience under nutrient stress

Summary / AbstractTo maintain lineage-specific functions, cells must acquire and allocate nutrients across diverse cellular processes, even in metabolically-dysregulated environments. The mechanisms allowing CD8+ T cells to maintain immune function in perturbed environments are poorly understood. We find that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reorient translational programming, limiting nutrient demand while prioritizing stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors ATF4 and CEBPG jointly establish an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial anaplerosis. Despite diminished energetic capacity under environmental stress, this program prevents failure of central carbon metabolism, mitigating stress amplification and cellular dysfunction to potentiate anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers functional resilience to immune cells in unfavorable environments, offering novel strategies to enhance immunotherapies.

immunology↗

bioRxiv2023

Tree-structured topic modelling of single-cell gene expression data uncovers hierarchical relationships between immune cell types

Immune cells undergo a series of differentiation steps following a lineage-tree structure stemming from hematopoietic stem cells. During differentiation of immune cells in both homeostasis and pathological processes, many gene regulatory mechanisms are shared by fully differentiated immune cell sub-types. In order to characterize these features quantitatively, we propose LaRCH, a tree-structured embedded topic model. In this model, single-cell gene expression profiles are represented by a mixture of topics consisting of latent features that follow an underlying tree structure, mirroring that of cellular differentiation-nested cluster structures. We present findings of our model trained on simulated single-cell RNA sequencing (scRNA-seq) based on cell-sorted bulk RNA-seq data as well as on a scRNA-seq dataset of over 1.2 million cells from healthy individuals and individuals diagnosed with systemic lupus erythematosus (SLE). The cellular topic profiles estimated by our model markedly improve clustering accuracy over traditional latent variable models and illustrate transcriptomic differences between SLE phenotypes, revealing a pivotal role of multiple immune cell types in disease progression and relapse. Ultimately, LaRCH captures the hierarchical context between cellular subtypes by simultaneously identifying shared and distinct latent features amongst subsets of heterogeneous samples of cells.

bioinformatics↗

bioRxiv2023

A multi-kingdom genetic barcoding system for precise target clone isolation

Clonal heterogeneity underlies diverse biological processes, including cancer progression, cell differentiation, and microbial evolution. Cell tagging strategies with DNA barcodes have recently enabled analysis of clone size dynamics and clone-restricted transcriptomic landscapes of heterogeneous populations. However, isolating a target clone that displays a specific phenotype from a complex population remains challenging. Here, we present a new multi-kingdom genetic barcoding system, CloneSelect, in which a target cell clone can be triggered to express a reporter gene for isolation through barcode-specific CRISPR base editing. In CloneSelect, cells are first barcoded and propagated so their subpopulation can be subjected to a given experiment. A clone that shows a phenotype or genotype of interest at a given time can then be isolated from the initial or subsequent cell pools stored throughout the experimental timecourse. This novel CRISPR-barcode genetics platform provides many new ways of analyzing and manipulating mammalian, yeast, and bacterial systems. TeaserA multi-kingdom CRISPR-activatable barcoding system enables the precise isolation of target barcode-labeled clones from a complex cell population.

synthetic biology↗