Biology subjects

Manrique-Castano, D.

Publications and source records attributed to Manrique-Castano, D..

3 recordsLinked to original sources

bioRxiv2026

Brain PDGFRβ+ cells exhibit diverse reactive phenotypes after stroke without requiring KLF4

Ischemic stroke triggers a cascade of molecular and cellular processes leading to fibrotic scar formation, entailing activation of brain platelet-derived growth factor receptor (PDGFR){beta}+ cells. Kruppel-like factor (KLF)4 plays an important role in regulating the activation of peripheral PDGFR{beta}+ perivascular cells in response to hypoxia/ischemia. Herein, we aimed to characterize the spatiotemporal responses of brain PDGFR{beta}+ cells while assessing the contribution of KLF4. This was achieved using transgenic mice that enable tracking or conditionally depleting KLF4 in PDGFR{beta}+ cells, which were subjected to experimental ischemic stroke. Next, we employed point pattern analysis (PPA) and topological data analysis (TDA) to quantitatively characterize cell phenotypic changes and spatial distribution over injury progression after ischemic stroke. We show that brain PDGFR{beta}+ cells rapidly become reactive and early localize to regions prone to irreversible damage. We report the emergence of parenchymal PDGFR{beta}+ cells, which cannot be causally linked to proliferation or vascular detachment. Moreover, our analysis reveals that KLF4 is barely expressed in brain PDGFR{beta}+ cells under normal conditions, and that its expression is slightly induced in reactive cells in the injured brain. Notably, specific attenuation of KLF4 induced expression in PDGFR{beta}+ cells does not affect cell reactivity and spatiotemporal distribution, nor scar formation and injury severity. These observations suggest that in contrast with the periphery, KLF4 is not implicated in regulating the responses of brain PDGFR{beta}+ cells. Our results indicate that the reactivity of brain PDGFR{beta}+ cells after stroke is spatiotemporally diverse, evolve over injury progression, and is distinct from peripheral perivascular cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/712632v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1149c62org.highwire.dtl.DTLVardef@26edaaorg.highwire.dtl.DTLVardef@1bd3d35org.highwire.dtl.DTLVardef@fd8030_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Dissecting glial scar formation by spatial point pattern and topological data analysis

Glial scar formation represents a fundamental response to central nervous system (CNS) injury. It is mainly characterized by a well-defined spatial rearrangement of reactive astrocytes and microglia. The mechanisms underlying glial scar formation have been extensively studied, yet quantitative descriptors of the spatial arrangement of reactive glial cells remain limited. Here, we present a novel approach using point pattern analysis (PPA) and topological data analysis (TDA) to quantify spatial patterns of reactive glial cells after experimental ischemic stroke in mice. We provide open and reproducible tools using R and Julia to quantify spatial intensity, cell covariance and conditional distribution, cell-to-cell interactions, and short/long-scale arrangement, which collectively disentangle the arrangement patterns of the glial scar. This approach unravels a substantial divergence in the distribution of reactive astrocytes and microglia after injury that conventional analysis methods cannot fully characterize. PPA and TDA are valuable tools for studying the complex spatial arrangement of reactive glia and other nervous cells following CNS injuries and have potential applications for evaluating glial-targeted restorative therapies.

neuroscience↗

bioRxiv2020

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABAB receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network activity. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory synapses. Significance statementThe question how the brains extracellular matrix (ECM) controls neuronal plasticity and network activity is key for an appropriate understanding of brain functioning. In this study, we demonstrate that ECM depletion much more strongly affects the integrity of inhibitory than excitatory synapses in vitro and in vivo. We revealed that by retaining inhibitory connectivity, ECM ensures the efficiency of inhibitory control over neuronal network activity. Our work significantly expands our current state of knowledge about the mechanisms of neuronal network activity regulation. Our findings are similarly relevant for researchers working on the physiological regulation of neuronal plasticity in vitro and in vivo and for researchers studying the remodeling of neuronal networks upon brain injury, where prominent ECM alterations occur.

neuroscience↗