【会议预告】Molecular Devices 与您相约全球再生医学研发创新与类器官研究峰会 2024

Abstract: 

Understanding the fundamental processes of human brain development and diseases is of great importance for our health. However, the translational potency for the knowledge obtained using traditional animal models remains limited due to species differences in the aspects of brain cytoarchitecture. Over the past years, an emerging model, the “brain organoid” integrated from human pluripotent stem cells, has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent, making it possible to better understand the complex structures and functions of the human brain. In this talk, I will present the applications of brain organoids in the understanding of human brain development and diseases, as well as our efforts put into brain organoid optimization, in particular vascularization.

Abstract: 

Intracranial tumors have poor prognosis, high recurrence rate and no standard treatment. This presentation will focus on how to overcome the critical issues of limited efficacy and high cost of conventional therapies in the treatment of malignant solid tumors. Mainly introduces the important innovations achieved by allogeneic CAR-T cell therapy in the treatment of intracranial solid tumors, through the advanced CRISPR gene editing technology and continuous optimization of cell therapy processes. We have successfully solved the core problems of allogeneic CAR-T cells in the treatment of solid tumors, such as rejection, poor efficacy and insufficient persistence, significantly reducing treatment costs and providing patients with more diverse and efficient treatment options.

Abstract: 

Biosensor is a powerful, label-free technique allowing us to perform analysis of molecular interactions in real-time. SPR spectroscopy can address questions such as specificity of an interaction, dissociation and association rate constants; binding kinetics, binding affinity, and concentrations of selected molecules present in a sample of interest. In this work, we report the novel SPR based cell/organoid integrated sensing platforms that allow us to real-time monitor cell and 3D tissue activities upon various of stimulations.  Using the novel set up, we measured and compared the binding affinity of vascular endothelial growth factor (VEGF) to vascular endothelial growth factor receptor (VEGFR) and VEGF to bevacizumab. Results have shown that bevacizumab binds VEGF with a higher association rate and affinity compared to VEGFR. Further, this platform has been employed to mimic the in vivo condition of the VEGF–VEGFR angiogenic switch. Competitive binding to VEGF between VEGFR and bevacizumab was monitored in real-time using this platform. The present invention provides surface plasmon resonance (SPR) based sensing systems and methods for rapid, sensitive, and real-time analysis of analyte secretion from living cells. In one embodiment, the SPR based sensing device of the present invention comprises at least one cell culture module for culturing living cells, wherein the cell culture module is configured so that analytes secreted from the living cells can be released onto a SPR sensing surface. The SPR based sensing system can perform a real-time analysis of one or more analytes secreted from the living cells by including a coating on the SPR sensing surface.   In addition, we have successfully demonstrated the use of surface plasmon resonance (SPR) technology to characterize the contractility of 3D cardiac tissues in response to Blebbistatin and ATP drug exposure in real time.

Abstract: 

Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA)mutations.However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG)mutatormice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

Abstract: 

Immune checkpoint blockade (ICB) opens the new era of cancer treatment, yet the heterogeneous nature of immune cells and their diverse spatial distributions demand novel techniques to decipher the local tumor immune microenvironment (TIME) to expand the patient groups benefiting from ICB. Here we generate primary lung cancer organoids (pLCOs) by isolating the tumor cell clusters, including the infiltrating immune cells, from dissected lung cancer samples. A FascRNA-seq platform allowing both the phenotypic evaluation and the scRNA-seq of all the single cells in an organoid was developed to dissect the TIME in individual pLCOs. Our analysis on 171 individual pLCOs derived from 7 patients revealed that pLCOs retained the fundamental features as well as the intra-tumor heterogeneity of local TIME in the parenchyma of parental tumor tissues, providing a series of models with the same genetic background but various TIME. Linking the single cell transcriptome data of individual pLCOs with their responses to ICB allowed us to confirm the central role of CD8+ Ts in ICB induced antitumor immunity, to identify the potential tumor-reactive T cells with a set of 10 genes, and to unravel the factors regulating T cell activity.

Abstract: 

Neural organoids are in vitro three-dimensional models that mimic the human brain or other structures of the nervous system. Beginning with stem cells, neural organoids are formed through unguided or guided neural differentiation under three-dimensional suspension culture conditions, relying on cell self-organization. In the past decade of research, we have focused on guided differentiation to construct various human brain region-specific organoids. Furthermore, by integrating multiple brain regions or cell lineages, we have explored the development of more complex human brain organoid technologies, providing new models for studying brain development, function, diseases, and drug effects in the context of human genetic backgrounds in vitro. As a cutting-edge technology, neural organoids still face various technical challenges that need to be overcome. This talk will introduce our efforts in the refined construction of human neural organoids, including how to build organoids that possess characteristics of human brain nuclei.

Abstract: 

The high cost and low success rate of drug development are major challenges, and there are significant differences between traditional preclinical biological models and the human physiopathology. Organ-on-a-chip technology as a novel model offers advantages for drug discovery, such as high biomimicry, low sample consumption, and high efficiency. We established microfluidic chip platforms for single-organ and multi-organ cultures. Based on these platforms, we developed over 20 highly biomimetic organ-on-a-chip models. These models have been applied in drug discovery and mechanism research. A notable achievement includes the pioneering use of tumor-on-a-chip models for the clinical application of cell therapy drug and dual-specificity antibody drug in China, marking a groundbreaking advancement in the field.

Abstract: 

Difficult and rare diseases have greatly hindered basic research and clinical diagnosis and treatment due to their small patient base, difficulty in medication, and unclear causes of onset. Xeroderma pigmentosum (XP) is a rare disease with birth defects. XP patients usually die before the age of 10, and there is currently no cure. We utilized the previously established skin organoid model to construct a human-induced pluripotent stem cell (hiPSC) derived XP skin organoid model from XP patients and a PDX model derived from XP organoid transplant mice. By combining multidimensional omics techniques such as single-cell transcriptome and spatial proteomics, we discovered a potential small molecule drug that can serve as a preventive measure against XP tumors after surgery.

Abstract: 

Choroidal atrophy is closely related to the development of age-related macular degeneration (AMD), retinitis pigmentosa, and pathological myopia. Studies suggested that choroidal endothelial cells (CECs) that form the choriocapillaris vessels are the first cells lost in choroidal atrophy. We found that endothelial cells derived from human pluripotent stem cells (hPSC-ECs) expressed CECs-specific markers and can integrate into choriocapillaris. scRNA-seq studies showed that hPSC-ECs upregulated angiogenesis and immune-modulatory and neural protective genes after interacting with ex vivo ischemic choroid. In a rat model of choroidal ischemia (CI), transplantation of hPSC-ECs into the suprachoroidal space increased choroid thickness and vasculature density. Close-up examination showed that engrafted hPSC-ECs integrated with all layers of choroidal vessels and lasted 90 days. Remarkably, EC transplantation improved the visual function of CI rats. Our work demonstrated that hPSC-ECs could repair choroidal ischemia, which may lead to a new therapy to alleviate choroidal atrophy implicated in dry AMD, pathological myopia, and other ocular diseases.

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