Probing Tissue Heterogeneity and Stem Cell Niche with Micro-Organospheres

用微有机球探测组织异质性和干细胞生态位

• 批准号: 10549220
• 负责人: Xiling Shen
• 金额: $ 68.2万
• 依托单位: TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549220
• 关键词: Adult; Basic Science; Cell Communication; Cell Lineage; Cells; Characteristics; Chimera organism; Communities; Development; Endothelial Cells; Engraftment; Epithelium; Growth; Heterogeneity; Homeostasis; Immune; Lead; Microbe; Process; Research; Research Technics; Stimulus; Techniques; Tissues; adult stem cell; cell type; combinatorial; deep learning algorithm; fundamental research; high throughput screening; host-microbe interactions; in vitro Model; indexing; intravital imaging; response; self renewing cell; self-renewal; stem cell differentiation; stem cell function; stem cell niche; stem cells; success; tool

Abstract Stem cells self-renew and differentiate into various cell lineages to sustain tissue homeostasis and functions. Most tissue microenvironments comprise multiple components, including epithelial, stromal, immune, and endothelial cells, that interact with each other to coordinate response to intrinsic and extrinsic stimuli. There remains an unmet need for in vitro models that can capture tissue heterogeneity and enable high-throughput studies. The PI developed Micro-OrganoSpheres (MOS) that can be established rapidly and efficiently from small amounts of primary tissues. Allowing self-renewal and differentiation of adult stem cells to recapitulate key tissue characteristics, MOS also sustain the original tissue microenvironment, enabling both ultra-high-throughput assays aided by deep-learning algorithms and direct microbial-host interactions. For the next R35 period, MOS will be leveraged as a fundamental research tool for understanding interactive processes in heterogeneous tissues in a systematic and scalable manner. Three projects are proposed: (1) We will set up a high-throughput MOS screen to systematically study how different cell types in a heterogenous tissue respond to different microbes. (2) We will develop a MOS combinatorial indexing technique to probe how cell-cell interactions in local microenvironments lead to spatially heterogenous tissue responses. (3) We will use MOS engraftment and intravital imaging to understand cell fate decisions and progression of stem cell niche from development to adulthood. The success of these projects will elucidate the mechanisms by which 1) different cells coordinate locally to respond to stimuli and 2) the stem cell niche progresses during growth. Furthermore, this research will provide the broader scientific community with basic research techniques that can be generalized to understand a wide variety of tissue and stem cell functions.

抽象的 干细胞自我更新并分化成各种细胞谱系以维持组织稳态和功能。 大多数组织微环境由多种成分组成，包括上皮、基质、免疫和 内皮细胞相互作用，协调对内在和外在刺激的反应。那里 对于能够捕获组织异质性并实现高通量的体外模型的需求仍然未得到满足 研究。 PI 开发了微有机球 (MOS)，可以从小规模快速高效地建立 原代组织的量。允许成体干细胞自我更新和分化以概括关键组织 特点，MOS还维持原有的组织微环境，从而实现超高通量 由深度学习算法和直接微生物-宿主相互作用辅助的测定。 在下一个 R35 时期，MOS 将被用作理解交互的基础研究工具 以系统且可扩展的方式在异质组织中进行过程。提议三个项目： (1) 我们将建立一个高通量MOS筛选系统来系统地研究不同细胞类型在 异质组织对不同的微生物有反应。 (2) 我们将开发一种 MOS 组合索引技术来探究局部细胞间的相互作用。 微环境导致空间异质的组织反应。 (3) 我们将使用MOS植入和活体成像来了解细胞命运决定和进展 干细胞生态位从发育到成年的过程。 这些项目的成功将阐明以下机制：1）不同的细胞在局部协调 对刺激作出反应；2) 干细胞生态位在生长过程中不断发展。此外，这项研究将提供 更广泛的科学界，拥有可以推广到广泛理解的基本研究技术 多种组织和干细胞功能。

项目成果

Spatial Patterning from an Integrated Wnt/β-catenin and Notch/Delta Gene Circuit.

集成 Wnt/β-连环蛋白和 Notch/Delta 基因电路的空间图案。

• DOI: 10.1109/embc.2018.8513462
• 发表时间: 2018
• 期刊: Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
• 作者: Mines,RobertC;Dohlman,Anders;Lim,Sze-Xian;Tung,Kuei-Ling;Wang,Ergang;Shen,Xiling
• 通讯作者: Shen,Xiling

The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.

• DOI: 10.1038/nature23676
• 发表时间: 2017-09-14
• 期刊: Nature
• 影响因子: 64.8
• 作者: Klose CSN;Mahlakõiv T;Moeller JB;Rankin LC;Flamar AL;Kabata H;Monticelli LA;Moriyama S;Putzel GG;Rakhilin N;Shen X;Kostenis E;König GM;Senda T;Carpenter D;Farber DL;Artis D
• 通讯作者: Artis D

Electrical stimulation of gut motility guided by an in silico model.

• DOI: 10.1088/1741-2552/aa86c8
• 发表时间: 2017-12
• 期刊: Journal of neural engineering
• 影响因子: 4
• 作者: Barth BB;Henriquez CS;Grill WM;Shen X
• 通讯作者: Shen X

Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts.

• DOI: 10.1371/journal.pcbi.1009811
• 发表时间: 2022-03
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Mines RC;Lipniacki T;Shen X
• 通讯作者: Shen X

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

• DOI: 10.1371/journal.ppat.1006974
• 发表时间: 2018-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Xu Y;Wang L;Zimmerman MD;Chen KY;Huang L;Fu DJ;Kaya F;Rakhilin N;Nazarova EV;Bu P;Dartois V;Russell DG;Shen X
• 通讯作者: Shen X