Biology subjects

Rostami, S.

Publications and source records attributed to Rostami, S..

7 recordsLinked to original sources

bioRxiv2026

Stress-adaptive biomaterials with tunable yielding architectures regulate organoid morphogenesis

The yield stress at which biomaterials undergo plastic deformation limits the stresses that can be developed in encapsulated growing tissues. While mechanical properties of the matrix such as stiffness and viscoelasticity have a profound effect on cells, the role of yield stress has remained challenging to define. Here we design a self-healing granular hydrogel platform with supramolecular host-guest dynamic crosslinkers to precisely and quantitatively tune the stress at which the matrix repeatedly yields and reconfigures around tissues as they grow. Designed to provide similar mechanical constraints as a mesh stress ball, matrix yield stresses can be tuned between 12 and 370 Pa, while maintaining a storage modulus below [~]0.1kPa. We show that this range of yield stress is sufficient to promote or limit peripheral shedding in a model of non-adhesive cancer migration; and that early development of midbrain organoids is exquisitely sensitive to yield stress. Optimal yield stresses of only 25 Pa promoted budlike protrusions and large, lumenized neural rosettes, while variations as small as 10 Pa limited these phenotypes. These studies demonstrate that morphogenesis and tissue organization are exquisitely sensitive to yield stress, suggesting a new material property to target in designing biomaterials for disease modeling and regenerative medicine.

biophysics↗

bioRxiv2025

Identification and characterization of Porphyromonas gingivalis TonB

Porphyromonas gingivalis is one of the major bacterial pathogens responsible for the initiation and progression of periodontal disease. The bacterium codes for multiple TonB-dependent receptors required for acquisition of nutrients such as heme and vitamin B12, although the identity of a TonB energy transducer has yet to be identified. Here we identify a potential TonB protein encoded by PG0785, generate a deficient strain, and characterize its biological significance. Bioinformatics analysis reveals that the PG0785 has unique features confined to the Cytophaga-Flavobacterium-Bacteroides (CFB) group of bacteria but shares similarities in the C-terminal domain (CTD) to well characterized proteins from Helicobacter pylori and Escherichia coli. Similarity at a protein level, as well as the genomic locus organization, was identified with the TonB proteins characterized in other Bacteroidota species. Loss of PG0785 led to significant alteration of the proteome: proteins mediating gene regulation, protein translation, protection against reactive radical species (oxygen and nitrogen), and glycosylation were up-regulated and polysaccharide export, efflux protein, and lipoproteins were downregulated. Furthermore, phenotypic studies showed that a mutant lacking PG0785 cannot accumulate heme on its surface and is deficient in gingipain protease activity. In addition, reduction of the capsular layer was detected in the TonB-deficient strain. Thus, while the mutant interacted and invaded eukaryotic cells at much higher levels than the wild type, it had significantly reduced ability to survive with host cells. ImportanceThe TonB system is indispensable for energy transduction in Gram-negative bacteria and is mainly associated with nutrient uptake. Although well investigated in Proteobacteria, the knowledge regarding the system in the CFB group of bacteria is lagging. In contrast to Proteobacteria, the intestinal Bacteroidota have multiple TonBs and their novel involvement in sugar utilization has been demonstrated. This study shows that the oral Bacteroidota, Porphyromonas gingivalis, also has TonB but unexpectedly, it is not involved in iron homeostasis or nutrient acquisition but rather in processes involved in maturation of proteases and cell surface remodeling. As maintenance of outer membrane integrity is mainly associated with Tol motor our study shows possible crosstalk between the energy transducers. Also, this study further demonstrates the functional versatility of the TonB system depending on the environmental niche and the metabolic requirements of the bacteria.

microbiology↗

bioRxiv2025

Heart-On-a-Chip with Integrated Ultrasoft Mechanosensors for Continuous Measurement of Cell- and Tissue-scale Contractile Stresses

Heart-on-a-chip platforms aim to miniaturize and replicate the complex structure and function of cardiac tissue. Traditionally, microfabricated pillar pairs have been employed in these systems to provide tissue anchorage and determine contractility parameters based on pillar deflection. However, this approach lacks the spatial resolution required to capture local cell- and tissue-scale mechanical stresses. In this study, we established a non-destructive optical method for continuous micro- and macro-scale contractile force measurements. We utilized our previously developed edge-labeled micro-spherical stress gauges (eMSGs) to map the stresses within a heart-on-a-chip. These ultrasoft mechanosensors visibly deform in response to stresses generated by cells and the extracellular matrix (ECM). The chip consisted of two cell-seeding chambers, each containing flexible silicone pillar pairs to support tissue formation and compaction. Neonatal rat cardiomyocytes (CMs) were encapsulated in a fibrin/Geltrex hydrogel mixture containing eMSGs and seeded into each chamber. Over time, the tissue compacted and began beating spontaneously, demonstrating structural alignment and functional cardiac hallmarks, such as calcium transients and tissue-scale beating. The effects of ECM composition on tissue function were examined, revealing that lower fibrin concentrations significantly enhanced contractile frequency, regularity, and stress generation. Local cell- and ECM-scale mechanics were further investigated by analyzing the shape changes of the dispersible sensors. Lateral and longitudinal stresses were calculated for each sensor, highlighting the critical role of tissue compaction and contraction in cell-generated forces. Finally, the platform was validated using two known drug candidates, with their effects on contractility clearly demonstrated.

bioengineering↗

bioRxiv2024

Aberrant TNF signaling in pancreatic lymph nodes of patients with Type 1 Diabetes

The therapeutic landscape for Type 1 Diabetes (T1D) is rapidly changing as ongoing clinical trials aim to delay beta-cell loss by inhibiting proinflammatory cytokines. However, the precise timing and cellular contexts of cytokine dysregulation remains unknown. We generated the largest existing measurement of gene expression and chromatin accessibility in [~]1 million immune cells from the pancreatic lymph nodes and spleens of 34 T1D and non-diabetic organ donors. Our study revealed heightened gene activity of the tumor necrosis factor (TNF) pathway and subsequent chromatin remodeling in central memory CD4+ T cells residing in the pancreatic lymph nodes of T1D and non-diabetic islet-autoantibody positive donors. These findings, validated in mice, offer a mechanism underlying the efficacy of TNF inhibitors, currently undergoing clinical trials to delay T1D onset.

immunology↗

bioRxiv2024

Directed biomechanical compressive forces enhance fusion efficiency in model placental trophoblast cultures

The syncytiotrophoblast is a multinucleated structure that arises from fusion of mononucleated cytotrophoblasts, to sheath the placental villi and regulate transport across the maternal-fetal interface. Here, we ask whether the dynamic mechanical forces that must arise during villous development might influence fusion, and explore this question using in vitro choriocarcinoma trophoblast models. We demonstrate that mechanical stress patterns arise around sites of localized fusion in cell monolayers, in patterns that match computational predictions of villous morphogenesis. We then externally apply these mechanical stress patterns to cell monolayers and demonstrate that equibiaxial compressive stresses (but not uniaxial or equibiaxial tensile stresses) enhance expression of the syndecan-1 marker of fusion. These findings suggest that the mechanical stresses that contribute towards sculpting the placental villi may also impact fusion in the developing tissue. We then extend this concept towards 3D cultures and demonstrate that fusion can be enhanced by applying low isometric compressive stresses to spheroid models, even in the absence of an inducing agent. These results indicate that mechanical stimulation is a potent activator of cellular fusion, suggesting novel avenues to improve experimental reproductive modelling, placental tissue engineering, and understanding disorders of pregnancy development.

biophysics↗

bioRxiv2021

Pre-Clinical Application of Functional Human Induced Pluripotent Stem Cell-Derived Airway Epithelial Grafts

Airway pathologies including cancer, trauma and stenosis lack effective treatments, meanwhile airway transplantation and available tissue engineering approaches fail due to epithelial dysfunction. Autologous progenitors do not meet the clinical need for regeneration due to their insufficient expansion and differentiation, for which human induced pluripotent stem cells (hiPSCs) are promising alternatives. Airway epithelial grafts are engineered by differentiating hiPSC-derived airway progenitors into physiological proportions of ciliated (73.9{+/-}5.5%) and goblet (2.1{+/-}1.4%) cells on a Silk Fibroin-Collagen Vitrigel Membrane (SF-CVM) composite biomaterial for transplantation in porcine tracheal defects ex vivo and in vivo. Evaluation of ex vivo tracheal repair using hiPSC-derived SF-CVM grafts demonstrate native-like tracheal epithelial metabolism and maintenance of mucociliary epithelium to day 3. In vivo studies reveal SF-CVM integration, maintenance of airway patency, showing 80.8{+/-}3.6% graft coverage with an hiPSC-derived pseudostratified epithelium and 70.7{+/-}2.3% coverage with viable cells, 3 days post-operatively. We demonstrate the utility of bioengineered, hiPSC-derived epithelial grafts for airway repair in a pre-clinical survival model, providing a significant leap for airway reconstruction approaches.

bioengineering↗

bioRxiv2021

Veillonella parvula: a strictly anaerobic bacterium with high efficacy for safe and specific tumor targeting and colonization

Bacterial cancer therapy has gained lots of attention in the past decade and is now considering a reliable option for the future. However, some concerns have limited its application into clinic settings like insufficient colonization of tumors and infectious origin of the currently used bacteria like Clostridium and Salmonella species, especially in cancer patients which exhibit different levels of immunocompromising. In the present study, Veillonella parvula (V. parvula) as a strictly anaerobic bacterium which has rarely identified as a pathogen in human, was administrated into 4T1 breast tumor-bearing mice. At first, 4T1 breast tumor-bearing BALB/c mice were injected with 107 bacteria intravenously, intraperitoneally, orally, or intratumorally. The best administration route according to tumor colonization and safety was selected. Then, the therapeutic effect of V. parvula administration was investigated according to the 4T1 breast tumors growth, metastasis, and tumor-bearing mice survival. Besides, histopathological evaluations were done to estimate microscopic changes at the inner of the tumor. V. parvula exhibited significant tumor-targeting and colonization efficacy, 24 h after intravenous administration and formed clustered colonies at the central region of the tumors. Although a negligible number of the bacteria were localized at normal organs, these organs became clear from the bacteria after 72 h, and no side effects or death were observed at the animals after intravenous administration of V. parvula. Although mean tumor volumes in the V. parvula treated group was lower than the control (~ 25.4%), their difference wasnt statistically significant (P > 0.05). Despite significant tumor colonization (5500000:1 in comparison with normal organs after 72 h), V. parvula didnt cause a significant therapeutic effect on the metastasis or survival time of tumor-bearing mice. Taking together, V. parvula is a completely safe and tumor-specific agent per se, without any genetic manipulation. Also, it exhibits high tumor penetration and colonization at the deep regions of the tumor.

cancer biology↗