Volume-dependent dose-response of the intestinal stem cell niche and lymphoid tissue

Emanuel Bahn; Michelle van Heerden; Karl Nicholas Sachse; John Gueulette; Jacobus P Slabbert; Markus Alber; William Shaw

doi:10.1016/j.radonc.2020.06.003

Volume-dependent dose-response of the intestinal stem cell niche and lymphoid tissue

Radiother Oncol. 2020 Sep:150:51-56. doi: 10.1016/j.radonc.2020.06.003. Epub 2020 Jun 10.

Authors

Emanuel Bahn¹, Michelle van Heerden², Karl Nicholas Sachse², John Gueulette³, Jacobus P Slabbert⁴, Markus Alber⁵, William Shaw²

Affiliations

¹ Department of Radiation Oncology, Heidelberg University Hospital, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: e.bahn@dkfz-heidelberg.de.
² University of the Free State, Department of Medical Physics (G68), Bloemfontein, South Africa.
³ Université Catholique de Louvain, Department of Molecular Imaging, Radiotherapy & Oncology (MIRO), Brussels, Belgium.
⁴ National Research Foundation, iThemba LABS, Cape Town, South Africa.
⁵ Department of Radiation Oncology, Heidelberg University Hospital, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany.

PMID: 32534012
DOI: 10.1016/j.radonc.2020.06.003

Abstract

Background and purpose: Plasticity of the intestinal stem cell compartment in response to radiation injury is regulated by a stem cell niche. We present here the first experimental observations of a dose-volume effect of the intestinal stem cell niche and of the solitary intestinal lymphoid tissues (SILT).

Materials and methods: Regeneration of intestinal crypts in mice was studied following irradiation of millimetre-size jejunal sections with single doses of 6 to 24 Gy and compared to total body irradiation (TBI). The statistical distribution of cells per crypt was scored and regressed to a biomathematical model. The number of SILTs was scored for different doses and field sizes and crypt regeneration was correlated with SILT proximity.

Results: We observed a differential dose-response of the intestinal stem cell niche at the centres of the irradiated sections, but only for field sizes below 10 mm. Irradiation of 5 mm jejunum results in an increase in crypt survival by up to an order of magnitude, compared to TBI. Distributions of cell-per-crypt numbers and comparison to biomathematical modelling suggest that these observations stem from a field size-dependent regeneration rate. The density of SILTs also exhibits a volume-dependent dose-response and increased crypt survival correlates with a proximity to SILTs.

Conclusion: Our findings present the first observation of a field-size dependent dose-response of the intestinal stem cell niche. Its regeneration process does apparently not rely on distant radiation-sensitive resources of the organism, such as the bone marrow. Yet, our observations suggest that the niche interacts with intact tissue in millimetres distance, leading to faster crypt regeneration. The field-size dependent dose-response of SILTs posits a role of the immune system on the dose-volume effect.

Keywords: Biomathematical modelling; Dose-volume effect; Immune system; Intestinal lymphoid tissue; Intestinal stem cells; Stem cell niche.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Intestinal Mucosa
Intestines*
Jejunum
Lymphoid Tissue
Mice
Stem Cell Niche*
Stem Cells