Rostami, S. | Search bioRxiv

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↗