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

Abstract

Sei Y, Feng J, Chow CC, Wank SA. Asymmetric cell divisiondominant 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 lineagetracing 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 lineagetraced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.

Tissue Adaptation to Environmental Cues by Symmetric and Asymmetric Division Modes of Intestinal Stem Cells

“…This main mode of division therefore leads to a neutral drift of the crypts, whereby progressive loss of ISC, when two TA are formed, is compensated by clonal expansion of the duplicated ISC. However, this model has recently been challenged by a study showing that the neutral drift is rather dominated by asymmetric cell division, which represents 60% of ISC division during normal homeostasis [ 25 ]. It is likely that this discrepancy results from the difference in food quality used in the two studies (see below).…”

“…From Drosophila to mammals, the choice between symmetric or asymmetric division of stem cells is determined by spindle orientation during mitosis [ 42 , 43 ]. In the mouse small intestine, symmetric and asymmetric cell divisions display spindle axes that are parallel or perpendicular to the basal surface, respectively [ 25 , 44 ]. Similarly, in the Drosophila intestine, the asymmetric division is guided by an oblique, nearly perpendicular position of the mitotic spindle relative to the basement membrane [ 13 , 28 ].…”

Cytoskeletal Control and Wnt Signaling—APC’s Dual Contributions in Stem Cell Division and Colorectal Cancer

“…However, this model has been challenged by lineage tracing studies proposing that cell division follows a stochastic pattern described as neutral drift dynamics, in which Lrg5+ divisions are predominantly symmetric and yield two cells with the same fate that potentially compete for space within the niche [ 128 ]. Yet, more recently, a counter-proposal has favoured instead an asymmetric cell division-dominant neutral drift model also validated in vivo [ 129 ]. These contrasting findings could be related to experimental details, e.g., nutrient availability, harsh environment or aging [ 124 , 130 ].…”

Rspo3 regulates abnormal differentiation of small intestinal epithelial cells in diabetic state

“…Intestinal stem cells (IESC) undergo dynamic differentiation from crypts to villi every 3-10 days. Study have found that the Lgr5 + crypt cells act as stem cells that reside at the crypt base regenerated normal IECs during homeostasis and are essential during regeneration [7]. Wnt signal pathway is a critical component of Lgr5 + crypt cells.…”