Biology subjects

Zhang, Z. J.

Publications and source records attributed to Zhang, Z. J..

8 recordsLinked to original sources

bioRxiv2026

Coalescing nephron and ureteric bud progenitors potentiates nephrogenesis in recellularized kidney scaffolds

Bioengineered, transplantable kidney tissue using decellularized scaffolds offers a promising strategy to overcome the shortage of donor kidneys that limits organ transplantation for patients with end stage renal disease. These kidney scaffolds retain essential extracellular matrix architecture, providing a biologically active niche for recellularization. Successful generation of bioengineered kidney tissues includes enhanced patent vasculature and mature, functional nephrons with collecting ducts. Here, we report the development of engineered kidney tissue consisting of reconstituted kidney scaffolds and human pluripotent stem cell-derived nephron and ureteric bud progenitors. Structural analysis of recellularized kidney scaffolds showed advanced nephron structures that became more mature and exhibited interconnected nephron and collecting ducts. In vivo engraftment of reconstituted kidney scaffolds in mice led to vascularization, maturation, and secretory function. Notably, mouse-graft vascular anastomosis was evident with erythrocytes present in vasculature and nephron-secreted proteins detected in mouse urine, indicating functional integration. This approach demonstrates the feasibility to generate advanced bioengineered kidney tissues that offer a versatile platform for disease modeling, drug screening, and regenerative medicine. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/733560v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@af021forg.highwire.dtl.DTLVardef@1b44feforg.highwire.dtl.DTLVardef@ebe73forg.highwire.dtl.DTLVardef@19b0acf_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Lantibiotic-producing bacteria impact microbiome resilience and colonization resistance

A subset of commensal bacterial strains secrete bacteriocins, such as lantibiotics, to establish and protect their niche in the gut. Because the antimicrobial spectrum of lantibiotics includes opportunistic pathogens, such as vancomycin-resistant Enterococcus faecium (VRE), they may provide an approach to reduce antibiotic-resistant infections. The impact of lantibiotic-producing bacteria on the complex microbial populations constituting the microbiome, however, remains poorly defined. We find that genes encoding lanthipeptides, including lantibiotics, are commonly present in the microbiomes of healthy humans and in dysbiotic microbiomes of hospitalized patients. In fecal samples collected from hospitalized patients, bacterial species encoding lantibiotic genes are present in greater abundance than lantibiotic-deficient strains of the same species. We demonstrate that the lantibiotic-producing bacterium, Blautia pseudococcoides SCSK, prevents intestinal recolonization of mice by a wide range of commensal species following antibiotic-induced dysbiosis and markedly reduces fecal concentrations of microbiota-derived metabolites associated with mucosal immune defenses. Lantibiotic-mediated dysbiosis results in sustained loss of colonization resistance against Klebsiella pneumoniae and Clostrioides difficile infection. Our findings reveal the potential impact of lantibiotic-producing bacterial species on microbiome resilience and susceptibility to infection following antibiotic treatment.

microbiology↗

bioRxiv2024

Comprehensive analyses of a large human gut Bacteroidales culture collection reveal species and strain level diversity and evolution

Species of the Bacteroidales order are among the most abundant and stable bacterial members of the human gut microbiome with diverse impacts on human health. While Bacteroidales strains and species are genomically and functionally diverse, order-wide comparative analyses are lacking. We cultured and sequenced the genomes of 408 Bacteroidales isolates from healthy human donors representing nine genera and 35 species and performed comparative genomic, gene-specific, mobile gene, and metabolomic analyses. Families, genera, and species could be grouped based on many distinctive features. However, we also show extensive DNA transfer between diverse families, allowing for shared traits and strain evolution. Inter- and intra-specific diversity is also apparent in the metabolomic profiling studies. This highly characterized and diverse Bacteroidales culture collection with strain-resolved genomic and metabolomic analyses can serve as a resource to facilitate informed selection of strains for microbiome reconstitution.

microbiology↗

bioRxiv2023

Exposure and resistance to lantibiotics impact microbiota composition and function

The intestinal microbiota is composed of hundreds of distinct microbial species that interact with each other and their mammalian host. Antibiotic exposure dramatically impacts microbiota compositions and leads to acquisition of antibiotic-resistance genes. Lantibiotics are ribosomally synthesized and post-translationally modified peptides produced by some bacterial strains to inhibit the growth of competing bacteria. Nisin A is a lantibiotic produced by Lactococcus lactis that is commonly added to food products to reduce contamination with Gram-positive pathogens. Little is known, however, about lantibiotic-resistance of commensal bacteria inhabiting the human intestine. Herein, we demonstrate that Nisin A administration to mice alters fecal microbiome compositions and the concentration of taurine-conjugated primary bile acids. Lantibiotic Resistance System genes (LRS) are encoded by lantibiotic-producing bacterial strains but, we show, are also prevalent in microbiomes across human cohorts spanning vastly different lifestyles and 5 continents. Bacterial strains encoding LRS have enhanced in vivo fitness upon dietary exposure to Nisin A but reduced fitness in the absence of lantibiotic pressure. Differential binding of host derived, secreted IgA contributes to fitness discordance between bacterial strains encoding or lacking LRS. Although LRS are associated with mobile genetic elements, sequence comparisons of LRS encoded by distinct bacterial species suggest they have been long-term components of their respective genomes. Our study reveals the prevalence, abundance and physiologic significance of an underappreciated subset of antimicrobial resistance genes encoded by commensal bacterial species constituting the human gut microbiome, and provides insights that will guide development of microbiome augmenting strategies.

microbiology↗

bioRxiv2023

Structure-Activity Relationship Studies of Novel Gut-derived Lantibiotics Against Human Gut Commensals

Recent advances in sequencing techniques unveiled the vast potential of ribosomally synthesized and post-translationally modified peptides (RiPPs) encoded in microbiomes. Class I lantibiotics such as nisin A, widely used as a food preservative, have been investigated for their efficacy in killing pathogens. However, the impact of nisin and nisin-like class I lantibiotics on commensal bacteria residing in the human gut remains unclear. Here, we report six gut-derived class I lantibiotics that are close homologs of nisin, four of which are novel. We applied an improved lantibiotic expression platform to produce and purify these lantibiotics for antimicrobial assays. We determined their minimal inhibitory concentration (MIC) against both Gram-positive human pathogens and gut commensals, and profiled the lantibiotic resistance genes in these pathogens and commensals. SAR studies with variants revealed key regions and residues that impact their antimicrobial properties. Our characterization and SAR studies of nisin-like lantibiotics against both pathogens and human gut commensals could shed light on the future development of lantibiotic-based therapeutics and food preservatives.

bioengineering↗

bioRxiv2022

Quantifying the mechanical properties of yeast Candida albicans using atomic force microscopy-based force spectroscopy

Fungi can adapt to a wide range of environmental stress in the wild and host milieu by employing their plastic genome and great diversity in morphology. Among different adaptive strategies, mechanical stimuli, such as changes in osmotic pressure, surface remodelling, hyphal formation, and cell divisions, could guide the physical cues into physiological responses through complex signalling network. While fungal pathogens require a pressure-driven force to expand and penetrate host tissues, quantitatively studying the biophysical properties at the host-fungal interface is critical to understand the development of fungal diseases. Microscopy-based techniques have enabled researchers to monitor the dynamic mechanics on fungal cell surface in responses to the host stress and antifungal drugs. Here, we describe a label-free, high-resolution method based on atomic force microscopy, with a step-by-step protocol to measure the physical properties in human fungal pathogen Candida albicans.

microbiology↗

bioRxiv2022

Engineered collagen-targeting therapeutics reverse lung and kidney fibrosis in mice

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving their therapeutic potential in mouse models of lung and kidney fibrosis. First, we identify and validate collagen-targeting drug delivery systems that preferentially accumulate in the diseased organs: von Willebrand Factors A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.

bioengineering↗

bioRxiv2021

Bone Marrow-Derived AXL Tyrosine Kinase Promotes Mitogenic Crosstalk and Cardiac Allograft Vasculopathy

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

immunology↗