Optimality in the development of intestinal crypts.
Intestinal crypts in mammals are comprised of long-lived stem cells and shorter-lived progenies. These two populations are maintained in specific proportions during adult life. Here, we investigate the design principles governing the dynamics of these proportions during crypt morphogenesis. Using optimal control theory, we show that a proliferation strategy known as a "bang-bang" control minimizes the time to obtain a mature crypt. This strategy consists of a surge of symmetric stem cell divisions, establishing the entire stem cell pool first, followed by a sharp transition to strictly asymmetric stem cell divisions, producing nonstem cells with a delay. We validate these predictions using lineage tracing and single-molecule fluorescence in situ hybridization of intestinal crypts in infant mice, uncovering small crypts that are entirely composed of Lgr5-labeled stem cells, which become a minority as crypts continue to grow. Our approach can be used to uncover similar design principles in other developmental systems.
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Shalev
S
Itzkovitz
Irene C
IC
Blat
Tyler
T
Jacks
Hans
H
Clevers
Alexander
A
van Oudenaarden
D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D007421:Intestine, Small / Q000166:cytology / Q000196:embryology / Q000254:growth & development*; D051379:Mice; D009024:Morphogenesis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled