Dissecting Fibroblast Heterogeneity in Health and Fibrotic Disease.

PURPOSE OF REVIEW: Fibroblasts, the major cell population in all connective tissues, are best known for their role in depositing and maintaining the extracellular matrix. Recently, numerous specialised functions have been discovered revealing unpredicted fibroblast heterogeneity. We will discuss this heterogeneity, from its origins in development to alterations in fibrotic disease conditions. RECENT FINDINGS: Advances in lineage tracing and single-cell transcriptional profiling techniques have revealed impressive diversity amongst fibroblasts in a range of organ systems including the skin, lung, kidney and heart. However, there are major challenges in assimilating the findings and understanding their functional significance. Certain fibroblast subsets can make specific contributions to healthy tissue functioning and to fibrotic disease processes; thus, therapeutic manipulation of particular subsets could be clinically beneficial. Here we propose that four key variables determine a fibroblast's phenotype underpinning their enormous heterogeneity: tissue status, regional features, microenvironment and cell state. We review these in different organ systems, highlighting the importance of understanding the divergent fibroblast properties and underlying mechanisms in tissue fibrosis

Fibroblast Memory in Development, Homeostasis and Disease

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair.

We have examined the developmental origins of Ng2+ perivascular cell populations that adhere to the basement membrane of blood vessels, and their contribution to wound healing. Neural/glial antigen 2 (Ng2) labeled most perivascular cells (70-80%) in developing and adult mouse back skin, a higher proportion than expressed by other pericyte markers Tbx18, Nestin and Pdgfrβ. In adult mouse back skin Ng2+ perivascular cells could be categorized into 4 populations based on whether they expressed Pdgfrα and Pdgfrβ individually or in combination or were Pdgfr-negative. Lineage tracing demonstrated that although Ng2+ cells in embryonic and neonatal back skin contributed to multiple cell types they did not give rise to interfollicular fibroblasts within the dermis. Lineage tracing of distinct fibroblast populations during skin development showed that papillary fibroblasts (Lrig1+) gave rise to Ng2+ perivascular cells in the upper dermis, whilst Ng2+ perivascular cells in the lower dermis were primarily derived from reticular Dlk1+ fibroblasts. Following wounding of adult skin, Ng2+ dermal cells only give rise to Ng2+ blood vessel associated cells and did not contribute to other fibroblast lineages. The relative abundance of Ng2+ Pdgfrβ+ perivascular populations was comparable in wounded and non-wounded skin, indicating that perivascular heterogeneity was maintained during full thickness skin repair. In the wound bed Ng2+ perivascular populations were primarily derived from Lrig1+ papillary or Dlk1+ reticular fibroblast lineages, according to the location of the regenerating blood vessels. We conclude that Ng2+ perivascular cells represent a heterogeneous lineage restricted population that is primarily recruited from the papillary or reticular fibroblast lineages during tissue regeneration

A Probiotic-Based Sanitation System for the Reduction of Healthcare Associated Infections and Antimicrobial Resistances: A Budget Impact Analysis

Healthcare Associated Infections (HAIs) and antibiotic resistance have high social and economic burdens. Healthcare environments play an important role in the transmission of HAIs. The Probiotic Cleaning Hygiene System (PCHS) showed to decrease hospital surface pathogens up to 90% vs. conventional chemical cleaning (CCC). This study compares PCHS to CCC as to reduction of HAIs and their severity, related antibiotic resistances, and costs. Incidence rates of HAIs/antibiotic resistances were estimated from a multicenter pre-post (6 months CCC + 6 months PCHS) intervention study after applying propensity score matching technique. A budget impact analysis compared the current scenario of use of CCC with future scenarios considering increasing utilization of PCHS, from 5% to 50% in the next five years, from the hospital perspective in Italy. The cumulative incidence of HAI was 4.6% and 2.4% (p <0.0001) for CCC (N=4,160) and PCHS (N=4,160) (OR = 0.47, CI 95% 0.37-0.60), with severe HAIs of 1.57% vs 1% and antibiotic resistances of 1.13% vs 0.53%, respectively. Increased use of PCHS over CCC in Italian internal medicine/geriatrics and neurology departments in the next 5 years is expected to avert at least about 31,000 HAIs and 8,500 antibiotic resistances, and save at least 14 million Euros, of which 11.6 for the treatment of resistant HAIs. Innovative, environmentally sustainable sanitation systems, like PCHS, might substantially reduce antibiotic resistance and increase protection of health worldwide

When a probiotic-based sanitizing method may halve healthcare-associated infections and reduce associated costs

No abstract availabl

Complete genome and plasmids sequences of a clinical Proteus mirabilis isolate producing plasmid mediated NDM-1 from Italy

Background: The spread of carbapenemase genes, such as blaNDM-1, in Proteus mirabilis poses a public health threat. The aim of the study was to characterize the genome and plasmids sequences of an NDM-1-positive strain (IBCRE14), which was isolated in 2019 from a catheterized patient hospitalized in Italy. Methods: Whole genome sequencing (WGS) of IBCRE14 was performed on extracted genomic DNA using Sequel I platform. Genome assembly was performed using “Microbial Assembly”. Genomic analysis was conducted by uploading the contigs to ResFinder and PlasmidFinder databases from the Center for Genomic Epidemiology. Results: IBCRE14 had a genome size of 4,018,329 bp and harboured genes coding for resistance to aminoglycosides (aadA1), phenicol (cat), tetracycline (tetJ), and trimethoprim (dfrA1). A large plasmid (pIB_NDM_1) harboured antibiotic resistance genes against sulphonamide (sul1), trimethoprim (dfrA14), tetracycline (tetB), rifampicin (arr-2), aminoglycosides (aadA1, aph3-VI), and beta-lactams (blaOXA-10, blaNDM-1). Furthermore, a small plasmid (pIB_COL3M) harboured a qnrD1 gene coding for quinolone resistance. Conclusion: The ability to conjugate and the presence of a composite antibiotic resistance island suggests that pIB_NDM_1 could both acquire more resistance genes and easily disseminate. To our knowledge, this is the first report on an untypable plasmid harbouring blaNDM-1 in P. mirabilis, in Italy

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

UK Medical Research Council (G1100073)Wellcome Trust (096540/Z/ 11/Z