Understanding stem cell heterogeneity and niche function in intestinal regeneration after irradiation

了解辐射后肠道再生中的干细胞异质性和生态位功能

• 批准号: 10910625
• 负责人: Chandan Guha
• 金额: $ 8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10910625
• 关键词: Academic Medical Centers; Ancillary Study; Applications Grants; Carrier Proteins; Cell Differentiation process; Cell Line; Cell Proliferation; Cell physiology; Cells; Child; Complement; Exhibits; FGF1 gene; FGFBP1 gene; Goals; Grant; Heterogeneity; Homeostasis; In Vitro; Intestines; Knowledge; LGR5 gene; Mediating; Medical Research; Medical center; Medicine; Methods; Modeling; Natural regeneration; Organoids; Parents; Population; Role; Rotavirus; Signal Transduction; Villus; Virus Diseases; WNT Signaling Pathway; base; cell motility; college; crypt cell; epithelium regeneration; in vivo; injury and repair; intestinal epithelium; irradiation; migration; mouse model; progenitor; regeneration following injury; regeneration potential; stem cell function; stem cells; tissue injury; tissue regeneration; tissue repair

ABSTRACT The intestinal epithelium exhibits rapid turnover mediated by intestinal stem cell (ISCs). Although Lgr5+ CBC cells have been well-accepted as the homeostatic ISC responsible for tissue regeneration, the Yan lab at Columbia University Medical Center has recently identified a putative new stem/progenitor cell located in the upper crypt “TA zone” region that is characterized by high-level expression of FGFBP1, a fibroblast growth factor carrier protein that is known to play a role in cell proliferation, differentiation, and migration. In vivo lineage tracing suggests Fgfbp1+ cells in the upper crypt give rise to Lgr5+ cells that repopulate the crypt base as well as cells that migrate in the opposite direction to replenish differentiated cells that line the villus that suggest their ISC function during homeostasis. However, the signals that regulate Fgfbp1+ cell function, their cellular role in tissue injury-repair, and our ability to harness their regenerative potential ex vivo remain completely unknown. Collaborative studies that leverage the collective expertise of the ISCC will address these gaps in our knowledge of Fgfbp1+ upper crypt cells using tissue injury models, diverse organoid platforms, and Wnt signaling niche manipulation. ISCC labs at Columbia, Cincinnati Children’s Medical Center, Stowers Institute for Medical Research, and our lab at Baylor College of Medicine (BCM) will collaboratively (1) Determine the cellular contribution of Fgfbp1+ cells in rotavirus-induced regeneration; (2) Determine the essential role of the Fzd 5 axis in Fgfbp1+ cells; and (3) Evaluate the ability of in vitro enteroid and organoid platforms to support Fgfbp1+ cells. These studies build on our ongoing studies in the parent U01 grant that are contributing to advancing the ISCC Trans-Consortium overarching goals of defining the essential niche component that contribute to intestinal epithelial homeostasis and that may play a role in epithelial regeneration following injury. These new ancillary studies complement our ongoing studies and use already established methods to evaluate the new ISC/progenitor population using new mouse models developed at Columbia University Medical Center.

摘要 肠上皮细胞具有由肠干细胞（ISCs）介导的快速更新。虽然LGR 5 + CBC细胞已被广泛接受为负责组织再生的稳态ISC， 哥伦比亚大学医学中心的Yan实验室最近发现了一种假定的新的干/祖细胞 位于上隐窝“TA区”区域的细胞，其特征在于高水平表达 FGFBP 1是一种已知在细胞增殖中起作用的成纤维细胞生长因子载体蛋白， 分化和迁移。体内谱系追踪表明，上隐窝中的Fgfbp 1+细胞引起 到Lgr 5+细胞，其重新填充隐窝基底以及以相反方向迁移的细胞， 补充排列在绒毛上的分化细胞，这表明它们在稳态期间具有ISC功能。 然而，调节Fgfbp 1+细胞功能的信号，它们在组织损伤修复中的细胞作用， 我们在体外利用其再生潜力的能力仍然完全未知。协同 利用信息系统协调委员会的集体专业知识进行的研究，将解决我们在以下方面的知识差距： 使用组织损伤模型、不同类器官平台和Wnt信号转导研究Fgfbp 1+上隐窝细胞 利基操纵哥伦比亚、辛辛那提儿童医学中心、Stowers研究所的ISCC实验室 医学研究，和我们在贝勒医学院（Baylor College of Medicine）的实验室将合作（1）确定 Fgfbp 1+细胞在轮状病毒诱导的再生中的细胞贡献;（2）确定Fgfbp 1+细胞在轮状病毒诱导的再生中的重要作用。 Fzd 5轴在Fgfbp 1+细胞中的作用;（3）评价体外肠样和类器官的能力 支持Fgfbp 1+细胞。这些研究建立在我们正在进行的U 01资助研究的基础上 这有助于推进ISCC跨联盟的总体目标， 一种重要的生态位成分，有助于肠上皮细胞的稳态，并可能发挥作用 在损伤后上皮再生中的作用。这些新的辅助研究补充了我们正在进行的研究 并使用已经建立的方法来评估新的ISC/祖细胞群体， 哥伦比亚大学医学中心开发的模型。

项目成果

Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth.

• DOI: 10.1242/dmm.049692
• 发表时间: 2023-04-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3

F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis

F4/80 Ly6Chigh 巨噬细胞导致结肠炎中的细胞可塑性和癌症发生

• DOI: 10.1053/j.gastro.2023.01.002
• 发表时间: 2023
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Shin Alice E.;Tesfagiorgis Yodit;Larsen Frederikke;Derouet Mathieu;Zeng Peter Y.F.;Good Hayley J.;Zhang Liyue;Rubinstein Mara R.;Han Yiping W.;Kerfoot Steven M.;Nichols Anthony C.;Hayakawa Yoku;Howlett Christopher J.;Wang Timothy C.;Asfaha Samuel
• 通讯作者: Asfaha Samuel

R‐spondin signaling in the stomach: isthmal Lgr4 rules

• DOI: 10.15252/embj.2022111696
• 发表时间: 2022-06
• 期刊: The EMBO Journal
• 作者: E. Malagola;Y. Hayakawa;T. Wang

BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice

• DOI: 10.1053/j.gastro.2018.11.024
• 发表时间: 2019-03-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Hayakawa, Yoku;Tsuboi, Mayo;Wang, Timothy C.
• 通讯作者: Wang, Timothy C.

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.

• DOI: 10.1016/j.ccell.2016.11.005
• 发表时间: 2017-01-09
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Hayakawa Y;Sakitani K;Konishi M;Asfaha S;Niikura R;Tomita H;Renz BW;Tailor Y;Macchini M;Middelhoff M;Jiang Z;Tanaka T;Dubeykovskaya ZA;Kim W;Chen X;Urbanska AM;Nagar K;Westphalen CB;Quante M;Lin CS;Gershon MD;Hara A;Zhao CM;Chen D;Worthley DL;Koike K;Wang TC
• 通讯作者: Wang TC