Biology subjects

Topilko, P.

Publications and source records attributed to Topilko, P..

4 recordsLinked to original sources

bioRxiv2025

Exploring the mechanisms governing the initiation of plexiform neurofibromas using Prss56Cre,Nf1-KO mouse model at a single-cell resolution

About half of patients with the genetic disease Neurofibromatosis type 1 (NF1) develop benign nerve sheath tumors, called plexiform neurofibromas (pNFs). Despite important advances in understanding the pathogenesis of pNFs, mainly due to the plethora of dedicated mouse models, the mechanisms responsible for the initiation of this process remain poorly understood. Here, we used a Nf1-KO mouse model targeting biallelic loss of Nf1 in boundary cap cells on a wild type and heterozygous Nf1 background to explore the early events driving pNFs development. All mutants develop subcutaneous hyperplastic nerves with some progressing into pNFs from one year of age. We discovered that skin trauma accelerates this process, highlighting the role of inflammation. While skin trauma has no effect on control subcutaneous nerves, in the mutant nerves on a wildtype background, we observed an expansion of mutant Schwann cells expressing a profibrotic program. A similar response was observed in the mutant nerves on a heterozygous background without skin trauma, highlighting the impact of Nf1 heterozygosity in the nerve micro-environment on the development of pNFs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/662123v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@18709d0org.highwire.dtl.DTLVardef@955a59org.highwire.dtl.DTLVardef@15e9bd2org.highwire.dtl.DTLVardef@481d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Hair follicle stem cell fate supports distinct clinical endotypes in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a severe skin disorder affecting 1% of the global population, with a complex and poorly understood pathogenesis involving aberrant keratinization and autoinflammation. It remains unclear whether autoinflammatory events precede or follow hyperkeratotic changes in hair follicle (HF) epithelia. Using single-cell RNA sequencing, we characterized HF cell populations in HS patients and investigated their role in disease pathogenesis. We uncovered two distinct differentiation trajectories of HF stem cells (HF-SCs): one leading to interfollicular epidermis (IFE) basal cells enriched in inflammatory pathways, and another giving rise to outer root sheath (ORS) cells associated with keratinization. In HS lesions, both populations displayed altered inflammatory phenotypes and were closely linked to immune cell infiltration, pointing to a role in disease heterogeneity. By integrating clinical features with HF cell composition from 49 HS patients, we identified three major endotypes: (i) an inflammatory subtype, marked by T cell infiltration and an expansion of IFE basal cells; (ii) a keratinizing subtype, characterized by ORS enrichment and minimal inflammation; and a mixed subtype, exhibiting features of follicular remodeling, fistula formation, and variable immune involvement. These findings provide novel insights into the epithelial-immune interactions that drive HS and support a stratified therapeutic approach tailored to the specific HF dysfunctions of each patient subgroup. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=49 SRC="FIGDIR/small/656362v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@4e8af9org.highwire.dtl.DTLVardef@85f61borg.highwire.dtl.DTLVardef@e085a7org.highwire.dtl.DTLVardef@66d804_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Myelinating Schwann cells and Netrin-1 control intra-nervous vascularization of the developing mouse sciatic nerve

Peripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during postnatal period.

developmental biology↗

bioRxiv2018

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling

Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. Data highlight for the first time that SC migrate preferentially along blood vessel in perivascular ECM, avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin receptor. Indeed, EphrinB3, enriched in myelin, interacts with SC Eph receptors, to drive SC away from CNS myelin, and triggers their preferential adhesion to ECM components, such as fibronectin via integrin{beta}1 interactions. This complex interplay enhances SC migration along the blood vessel network and together with lesion-induced vascular remodeling facilitates their timely invasion of the lesion site. These novel findings elucidate the mechanism by which SC invade and contribute to spinal cord repair.

neuroscience↗