Asymmetric cell division-dominant neutral drift model for normal intestinal stem cell homeostasis

The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineage-tracing studies in mice shows that the symmetric cell division-dominant...

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Bibliographic Details
Published in:American journal of physiology: Gastrointestinal and liver physiology 2019-01, Vol.316 (1), p.G64-G74
Main Authors: Sei, Yoshitatsu, Feng, Jianying, Chow, Carson C, Wank, Stephen A
Format: Article
Language:English
Subjects:
Animal models
Animals
Asymmetric Cell Division - physiology
Cell Differentiation - physiology
Cell division
Cell Lineage - physiology
Cells, Cultured
Drift
Epithelium
Homeostasis
Homeostasis - physiology
Intestinal Mucosa - cytology
Intestine
Intestines - cytology
Mathematical models
Mice
Regeneration - physiology
Small intestine
Stem cell transplantation
Stem cells
Stem Cells - cytology
Stochasticity
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Summary:The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineage-tracing studies in mice shows that the symmetric cell division-dominant neutral drift model fits well with the observed in vivo growth of ISC clones and suggests that symmetric divisions are central to ISC homeostasis. However, other studies suggest a critical role for asymmetric cell division in the maintenance of ISC homeostasis in vivo. Here, we show that the stochastic branching and Moran process models with both a symmetric and asymmetric division mode not only simulate the stochastic growth of the ISC clone in silico but also closely fit the in vivo stem cell dynamics observed in lineage-tracing studies. In addition, the proposed model with highest probability for asymmetric division is more consistent with in vivo observations reported here and by others. Our in vivo studies of mitotic spindle orientations and lineage-traced progeny pairs indicate that asymmetric cell division is a dominant mode used by ISCs under normal homeostasis. Therefore, we propose the asymmetric cell division-dominant neutral drift model for normal ISC homeostasis. NEW & NOTEWORTHY The prevailing mathematical model suggests that intestinal stem cells (ISCs) divide symmetrically. The present study provides evidence that asymmetric cell division is the major contributor to ISC maintenance and thus proposes an asymmetric cell division-dominant neutral drift model. Consistent with this model, in vivo studies of mitotic spindle orientation and lineage-traced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00242.2018