Biology subjects

Romero-Mulero, M. C.

Publications and source records attributed to Romero-Mulero, M. C..

3 recordsLinked to original sources

bioRxiv2026

Intravital microscopy and statistical image analysis of early engraftment of haematopoietic stem cells reveal dynamic and evolving cellular behaviours linked to progressive differentiation.

Haematopoietic stem cells (HSCs) have long been used in the clinic for bone marrow transplantation applications, critical for the survival of an increasingly wide range of patients with haematological, oncological and immunological pathologies. Despite this, little is known about the mechanisms through which relatively few stem cells are able to regenerate the entire haematopoietic tissue of transplant recipients. To gain insights on this biological process, we used intravital microscopy of calvarium bone marrow, collecting tissue-wide images and a total of 850 hours of tracks of engrafting haematopoietic stem and progenitor cells from 24 hours to 8 days following injection in lethally irradiated recipients. Analysis of the data revealed that regenerating HSCs and their immediate progeny are highly dynamic, migrating through the parenchyma at both the microscopic and near-macroscopic scales, i.e. within and in-and-out of fields of view. HSC-derived cell clusters, expanded locally between day 2 and day 4 post-transplant, leading to patches of densely populated bone marrow by day 8. Single cell level analysis highlighted increasingly heterogenous cellular behaviours over time. Track clustering based on migration and niche interaction parameters combined with post-tracking whole mount immunostaining revealed that persistence in the vicinity of nestin-GFP perivascular cells and relatively slow movement correlated with stemness, while more heterogeneous niche interactions coupled with slowest or faster migration correlated with differentiation, validated through flow cytometry analysis and functional studies. The findings presented here shed light on the fundamental principles driving haematopoietic regeneration in transplantation settings.

developmental biology↗

bioRxiv2022

Prenatal inflammation perturbs fetal hematopoietic development and causes persistent changes to postnatal immunity

Adult hematopoietic stem and progenitor cells (HSPCs) respond directly to inflammation and infection, resulting in both acute and persistent changes to quiescence, mobilization, and differentiation. Here we show that fetal HSPCs respond to prenatal inflammation in utero, and that the fetal response shapes postnatal hematopoiesis and immunity. Heterogenous fetal HSPCs showed divergent responses to maternal immune activation (MIA), including changes in quiescence, expansion, and lineage-biased output. Single cell transcriptomic analysis of fetal HSPCs in response to MIA revealed specific upregulation of inflammatory gene profiles in discrete, transient HSC populations, that propagated expansion of lymphoid-biased progenitors. Beyond fetal development, MIA caused the inappropriate expansion and persistence of fetal lymphoid-biased progenitors postnatally, concomitant with increased cellularity and hyperresponsiveness of fetal-derived innate-like lymphocytes. Our investigation demonstrates how inflammation in utero can direct the trajectory of output and function of fetal-derived immune cells by reshaping fetal HSC establishment.

cell biology↗

bioRxiv2020

ULK1 and ULK2 are less redundant than previously thought: Computational analysis uncovers distinct regulation and functions of these autophagy induction proteins

Macroautophagy, the degradation of cytoplasmic content by lysosomal fusion, is an evolutionary conserved process promoting homeostasis and intracellular defence. Macroautophagy is initiated primarily by a complex containing ULK1 or ULK2 (two paralogs of the yeast Atg1 protein). Deletion of ULK1 is sufficient to interrupt autophagy, while ULK2 seems expendable. To understand the differences between ULK1 and ULK2, we compared the human ULK1 and ULK2 proteins and their regulation. Despite the high similarity in their enzymatic domain, we found that ULK1 and ULK2 have major differences in their post-translational and transcriptional regulators. We identified 18 ULK1-specific and 7 ULK2-specific protein motifs serving as different interaction interfaces. We identified three ULK1-specific and one ULK2-specific transcription factor binding sites, and eight sites shared by the regulatory region of both genes. Importantly, we found that both their post-translational and transcriptional regulators are involved in distinct biological processes - suggesting separate functions for ULK1 and ULK2. For example, we found a condition-specific, opposite effect on apoptosis regulation for the two ULK proteins. Given the importance of autophagy in diseases such as inflammatory bowel disease and cancer, unravelling differences between ULK1 and ULK2 could lead to a better understanding of how autophagy is dysregulated in diseased conditions.

molecular biology↗