TY - JOUR
T1 - Optimality in the development of intestinal crypts
AU - Itzkovitz, Shalev
AU - Blat, Irene C.
AU - Jacks, Tyler
AU - Clevers, Hans
AU - Van Oudenaarden, Alexander
N1 - NIH/NCI Physical Sciences Oncology Center at MIT [U54CA143874]; NIH [1DP1OD003936]; National Cancer Institute [P30-CA14051]; International Human Frontiers Science Program Organization; Machiah Foundation; Howard Hughes Medical Institute We thank Uri Alon for suggesting the optimality problem. We thank Johan van Es for help with the lineage tracing experiments. We also thank George Oster, Hyun Youk, Stefan Semrau and Sandy Klemm for valuable discussions. This work was supported by the NIH/NCI Physical Sciences Oncology Center at MIT (U54CA143874) and a NIH Pioneer award (1DP1OD003936) to A.v.O. and in part by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. T.J. is a Howard Hughes Investigator and a Daniel K. Ludwig Scholar. S.I. acknowledges support from the International Human Frontiers Science Program Organization and the Machiah Foundation. I.B. acknowledges support from the Howard Hughes Medical Institute Gilliam fellowship.
PY - 2012/2/3
Y1 - 2012/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856762359&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cell.2011.12.025
DO - https://doi.org/10.1016/j.cell.2011.12.025
M3 - مقالة
SN - 0092-8674
VL - 148
SP - 608
EP - 619
JO - Cell
JF - Cell
IS - 3
ER -