The intestinal epithelium is rapidly renewed every 3-5 days from both active cycling stem cells, as well as, more quiescent stem cells. The radiation-induced gastrointestinal syndrome (RIGS) results from dose-dependent, cytocidal effects of radiation on intestinal stem cells. Preliminary work from our group has demonstrated using inducible Cre-dependent lineage tracing that Keratin-19 (Krt19) labels intestinal stem cells distinct from Lgr5+ CBCs and located above the +4 region. In contrast to Lgr5+ cells, Krt19+ stem cells are radioresistant and can regenerate the small intestine following 12Gy radiation. In addition, data from our group has shown that both mesenchymal cells and nerves are important in modulating stem cells and contributing to regeneration. Thus, it is our hypothesis that the +4 intestinal stem cell (ISC) marked by Krt19 is critical to the response to radiation injury, and maybe regulated by stromal factors distinct from that for Lgr5+ stem cells. We will explore this hypothesis through three specific aims. (1) What is the hierarchical relationship and characteristics that distinguish Lgr5+ and Krt19+ stem cells. We will use in vivo lineage tracing, in vitro organoids and gene expression studies to explore these distinct stem cell populations. (2) What is the role of neural factors in ISC expansion in response to radiation injury? We will use murine models with altered serotonin and cholinergic signaling to assess the response of ISCs to radiation injury. (3) How do intestinal growth factors regulate ISC regeneration in mice after radiation? We will examine defined intestinal growth factors (such as R-spondin1 and KGF), as well as other candidate niche factors, in the protection and mitigation of RIGS. There are currently no approved medical countermeasures to alleviate the RIGS. Overall, this proposal will investigate the hierarchy, cell fate, and role in regeneration of various ISC populations post radiation.

Public Health Relevance

In this study, we plan to study the role of Krt19+ versus Lgr5+ stem cells in the radiation- induced gastrointestinal syndrome (RIGS) that results from cytocidal effects of radiation on intestinal stem cells. We have demonstrated differences in radiosensitivities among these two stem cell populations, and hypothesize that different neural and/or stromal niche factors regulate the two stem cell pools in distinct manners. Thus, we aim to characterize Krt19+ versus Lgr5+ stem cells in the epithelial radiation response and identify novel therapeutic agents for radiation-induced gastrointestinal injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Hayakawa, Yoku; Tsuboi, Mayo; Asfaha, Samuel et al. (2018) BHLHA15-positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. Gastroenterology :
Hayakawa, Yoku; Sakitani, Kosuke; Konishi, Mitsuru et al. (2017) Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell 31:21-34
Kulkarni, Shilpa; Wang, Timothy C; Guha, Chandan (2016) Stromal Progenitor Cells in Mitigation of Non-Hematopoietic Radiation Injuries. Curr Pathobiol Rep 4:221-230
Saha, Subhrajit; Aranda, Evelyn; Hayakawa, Yoku et al. (2016) Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nat Commun 7:13096
Asfaha, Samuel; Hayakawa, Yoku; Muley, Ashlesha et al. (2015) Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine. Cell Stem Cell 16:627-38