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.

摘要 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。 大多数组织微环境包含多种组分，包括上皮、基质、免疫和微环境。 内皮细胞，它们相互作用以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能够实现高通量的体外模型， 问题研究 PI开发了微有机球体（MOS），可以从小到大快速有效地建立 大量的初级组织。允许成体干细胞的自我更新和分化重演关键组织 MOS还维持原始组织微环境，实现超高通量 通过深度学习算法和直接微生物-宿主相互作用辅助的分析。 在下一个R35期间，MOS将被用作理解互动的基础研究工具。 以系统和可扩展的方式在异质组织中进行处理。建议开展三个项目： (1)我们将建立一个高通量的MOS筛选，系统地研究不同类型的细胞在一个 异种组织对不同微生物有反应。 (2)我们将开发一种MOS组合索引技术，以探测细胞间的相互作用如何在局部 微环境导致空间异质组织反应。 (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 从发育到成年的干细胞生态位。 这些项目的成功将阐明1）不同细胞局部协调的机制， 对刺激作出反应和2）干细胞龛在生长期间进展。此外，这项研究将提供 更广泛的科学界与基本的研究技术，可以概括为了解广泛的 各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

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

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