Biology subjects

Mazin, P.

Publications and source records attributed to Mazin, P..

9 recordsLinked to original sources

bioRxiv2025

Pathogenic Keratinocyte States and Fibroblast Niches Define the Tissue Microenvironment in Severe Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful abscesses and tunnels in flexural sites. The mechanisms driving HS pathogenesis, particularly the roles of keratinocytes and fibroblasts in the HS inflammatory microenvironment, remain poorly understood. To characterise the cellular and molecular landscape of HS, we analyzed lesional skin from severe HS patients using single-cell RNA-sequencing and spatial transcriptomics to identify keratinocyte states and patterns of cellular interactions, with a focus on fibroblast-keratinocyte crosstalk. We identified a migratory S100+ pathogenic keratinocyte state enriched in HS lesions and observed spatially distinct fibroblast populations associated with different tissue compartments. COL6A5+ fibroblasts were preferentially co-localised with undifferentiated keratinocyte states, whereas APOD+ fibroblasts with enriched in immune cell-rich regions containing activated B and plasma cells consistent with tertiary lymphoid organ (TLO)-like structures. Ligand-receptor inference and spatial co-localisation analyses predicted extensive fibroblast-keratinocyte and fibroblast-immune interactions within HS lesions. Together, these data define the cellular organisation of the HS tissue microenvironment and identify spatially distinct stromal and epithelial niches associated with severe disease. These findings provide a framework for understanding how epithelial, stromal and immune cell populations coexist within HS lesions and may help to explain the limited efficacy of therapies targeting individual inflammatory pathways in the treatment of HS.

cell biology↗

bioRxiv2024

A single cell and spatial genomics atlas of human skin fibroblasts in health and disease

Fibroblasts are critical cells that shape the architecture and cellular ecosystems in multiple tissues. Understanding fibroblast heterogeneity and their spatial context in health and disease has enormous clinical relevance. In this study, we constructed a spatially-resolved atlas of human skin fibroblasts from healthy skin and 23 skin disorders. We define 6 major skin fibroblast populations in health and a further three skin disease-specific fibroblast subtypes, and demonstrate the fibroblast composition in different types of skin disease. We characterise a human-specific fibroblastic reticular cell (FRC)-like subtype in the skin perivascular niche and postulate their origin from prenatal skin lymphoid tissue organiser (LTo)-like cells. We also show that inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) are a conserved fibroblast subtype in inflammatory disorders and cancers across multiple human tissues. We provide a harmonised nomenclature for skin fibroblasts that integrates previous findings from human skin and other tissues.

cell biology↗

bioRxiv2024

A developmental cell atlas of the human thyroid gland

The primary function of the thyroid gland is the synthesis and release of thyroid hormones, which are essential for health from embryogenesis to adulthood. Thyroid disorders occur frequently and include congenital hypothyroidism, which occurs due to aberrant thyroid development (thyroid dysgenesis) or impaired hormone synthesis and is particularly prevalent in trisomy 21 (T21). In contrast, thyroid carcinoma, an acquired disorder, is the most common endocrine malignancy in both paediatric and adult populations. Understanding the molecular basis of thyroid dysgenesis and paediatric thyroid carcinoma remains challenging, and requires an improved understanding of foetal thyroid development. To address this, we generated a comprehensive spatiotemporal atlas of the human thyroid during the first and second trimesters of pregnancy. Profiling over 200,000 cells with single-cell sequencing revealed key cell types involved in thyroid gland development, including the hormone-producing thyrocytes. We discovered that foetal thyroid follicular cells are heterogeneous epithelial populations consisting of two main functional subtypes (fTFC1, fTFC2), with fTFC2 expressing increased levels of PAX8, and spatial transcriptomics revealed subtype co-occurrence within individual follicles. While both fTFC1 and fTFC2 persist in adult thyroid, fTFC2 is a minor population amongst additional PAX8-positive follicular cell subsets. We observed thyroid dysgenesis in T21 age-matched specimens, and T21 thyrocytes showed transcriptional signatures of cytoskeletal disorganisation and altered interactions with the extracellular matrix, as well as compensatory activation of metabolic stress gene programs and upregulation of thyroid biosynthetic genes. In line with the altered proportions of fTFC2 in healthy foetal and adult thyroid, papillary thyroid cancer in children is transcriptionally enriched for the fTFC2 signature compared to that in adults. All together, these findings reveal thyrocyte heterogeneity across the lifespan and provide insights into thyroid development in health and disease, informing potential therapeutic interventions.

genomics↗

bioRxiv2024

A multiomic atlas of human early skeletal development

Bone and joint formation in the developing skeleton rely on co-ordinated differentiation of progenitors in the nascent developing limbs and joints. The cell states, epigenetic processes and key regulatory factors underlying their lineage commitment to osteogenic and other mesenchymal populations during ossification and joint formation remain poorly understood and are largely unexplored in human studies. Here, we apply paired single-nuclei transcriptional and epigenetic profiling of 336,000 droplets, in addition to spatial transcriptomics, to construct a comprehensive atlas of human bone, cartilage and joint development in the shoulder, hip, knee and cranium from 5 to 11 post-conception weeks. Spatial mapping of cell clusters to our highly multiplexed in situ sequencing (ISS) data using our newly developed tool ISS-Patcher revealed new cellular mechanisms of zonation during bone and joint formation. Combined modelling of chromatin accessibility and RNA expression allowed the identification of the transcriptional and epigenetic regulatory landscapes that drive differentiation of mesenchymal lineages including osteogenic and chondrogenic lineages, and novel chondrocyte cell states. In particular, we define regionally distinct limb and cranial osteoprogenitor populations and trajectories across the fetal skeleton and characterise differential regulatory networks that govern intramembranous and endochondral ossification. We also introduce SNP2Cell, a tool to link cell-type specific regulatory networks to numerous polygenic traits such as osteoarthritis. We also conduct in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential pathogenic cell states and disease mechanisms involved. This work forms a detailed and dynamic regulatory atlas of human fetal skeletal maturation and advances our fundamental understanding of cell fate determination in human skeletal development.

developmental biology↗

bioRxiv2023

A rapid method for generating transplantable and biologically responsive colonic tissue from human induced pluripotent stem cells.

BackgroundThe colonic mucosa consists of cell populations derived from multiple lineages. Induced pluripotent stem cells (iPSCs) are capable of generating large numbers of differentiated cells from any lineage. Thus, iPSCs are highly versatile for derivation of intestinal cells for generation of colonic mucosal tissue for clinical and biological applications. ObjectiveWe set out to create a human iPSC (hiPSC) multi-lineage co-differentiation platform capable of generating colonic mucosal tissue in vitro. DesignWe used hiPSCs and designed a differentiation protocol consisting of small molecules and recombinant growth factors to generate multiple cell lineages. Cells were seeded onto collagen hydrogels (forming colonic patches - CoPs) and modulated with multiple growth factors important in intestinal biology. CoPs were transplanted into immunosuppressed mice. Generated cells and tissues were profiled with transcriptomic analysis. ResultshiPSC co-differentiation led to multiple intestinal epithelial, mesenchymal and endothelial cell populations. Seeded onto collagen scaffolds these cells created CoPs, which were transplanted into mouse subcutis. Engrafted CoPs developed into normal-looking colonic mucosa containing epithelial crypts (with enterocytes, goblet cells and neuroendocrine cells), multiple lamina propria-resident stromal populations and muscularis mucosae smooth muscle. They anastomosed to murine vasculature and maintained in-vitro for several weeks. We demonstrated that CoPs respond to known signalling pathways important in colonic mucosal biology and fibrogenesis, showing potential to provide a complex model of colonic pathobiology. ConclusionThis platform could offer an accurate model of intestinal pathobiology, supply cells for regenerative cell therapies to treat intestinal disease, and provide therapeutic autologous grafts to repair damaged colon.

cell biology↗

bioRxiv2023

Cutaneous T cell lymphoma atlas reveals malignant Th2 cells supported by a B cell-rich microenvironment

Cutaneous T-cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides (MF), can be difficult to diagnose resulting in treatment delay. The pathogenesis of CTCL is not fully understood due to limited data from patient studies. We performed single-cell RNA sequencing and spatial transcriptomics profiling of skin from patients with MF-type CTCL, and an integrated comparative analysis with human skin cell atlas datasets from healthy skin, atopic dermatitis and psoriasis. We reveal the co-optation of Th2-immune gene programmes by malignant CTCL cells and modelling of the tumour microenvironment to support their survival. We identify MHC-II+ fibroblast subsets reminiscent of lymph node T-zone reticular cells and monocyte-derived dendritic cells that can maintain Th2-like tumour cells. CTCL Th2-like tumour cells are spatially associated with B cells, forming aggregates reminiscent of tertiary lymphoid structures which are more prominent with progressive disease. Finally, we validated the enrichment of B cells in CTCL skin infiltrates and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

genomics↗

bioRxiv2023

Multi-scale spatial mapping of cell populations across anatomical sites in healthy human skin and basal cell carcinoma

Our understanding of how human skin cells differ according to anatomical site and tumour formation is limited. To address this we have created a multi-scale spatial atlas of healthy skin and basal cell carcinoma (BCC), incorporating in vivo optical coherence tomography, single cell RNA sequencing, spatial global transcriptional profiling and in situ sequencing. Computational spatial deconvolution and projection revealed the localisation of distinct cell populations to specific tissue contexts. Although cell populations were conserved between healthy anatomical sites and in BCC, mesenchymal cell populations including fibroblasts and pericytes retained signatures of developmental origin. Spatial profiling and in silico lineage tracing support a hair follicle origin for BCC and demonstrate that cancer-associated fibroblasts are an expansion of a POSTN+ subpopulation associated with hair follicles in healthy skin. RGS5+ pericytes are also expanded in BCC suggesting a role in vascular remodelling. We propose that the identity of mesenchymal cell populations is regulated by signals emanating from adjacent structures and that these signals are repurposed to promote the expansion of skin cancer stroma. The resource we have created is publicly available in an interactive format for the research community. Significance statementSingle cells RNA sequencing has revolutionised cell biology, enabling high resolution analysis of cell types and states within human tissues. Here, we report a comprehensive spatial atlas of adult human skin across different anatomical sites and basal cell carcinoma (BCC) - the most common form of skin cancer - encompassing in vivo optical coherence tomography, single cell RNA sequencing, global spatial transcriptomic profiling and in situ sequencing. In combination these modalities have allowed us to assemble a comprehensive nuclear-resolution atlas of cellular identity in health and disease.

cell biology↗

bioRxiv2022

Multi-organ functions of yolk sac during human early development

The yolk sac (YS) represents an evolutionarily-conserved extraembryonic structure that ensures timely delivery of nutritional support and oxygen to the developing embryo. However, the YS remains ill-defined in humans. We therefore assemble a complete single cell 3D map of human YS from 3-8 post conception weeks by integrating multiomic protein and gene expression data. We reveal the YS as a site of primitive and definitive haematopoiesis including a YS-specific accelerated route to macrophage production, a source of nutritional/metabolic support and a regulator of oxygen-carrying capacity. We reconstruct the emergence of primitive haematopoietic stem and progenitor cells from YS hemogenic endothelium and their decline upon stromal support modulation as intraembryonic organs specialise to assume these functions. The YS therefore functions as three organs in one revealing a multifaceted relay of vital organismal functions as pregnancy proceeds. One Sentence SummaryHuman yolk sac is a key staging post in a relay of vital organismal functions during human pregnancy.

developmental biology↗

bioRxiv2019

Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains

Identification of gene expression traits unique to the human brain sheds light on the mechanisms of human cognition. Here we searched for gene expression traits separating humans from other primates by analyzing 88,047 cell nuclei and 422 tissue samples representing 33 brain regions of humans, chimpanzees, bonobos, and macaques. We show that gene expression evolves rapidly within cell types, with more than two-thirds of cell type-specific differences not detected using conventional RNA sequencing of tissue samples. Neurons tend to evolve faster in all hominids, but non-neuronal cell types, such as astrocytes and oligodendrocyte progenitors, show more differences on the human lineage, including alterations of spatial distribution across neocortical layers.

evolutionary biology↗