Our studies of 15 adjacent crypt pairs suggest most crypt pairs will be unrelated, consistent with low frequencies of somatically acquired human crypt clusters.
Under these culture conditions, single crypts undergo multiple crypt fission events, while simultaneously generating villus-like epithelial domains in which all differentiated cell types are present.
By comparing the frequencies of different crypt clusters (Fig 3C and F), we found the induction frequency (resulting in monoclonal crypts) for WT mice was set by p 0 WT = 0.006 ± 0.002 per crypt.
Multiple crypts surrounded each crypt, and even if two adjacent crypts were recently related, it would be difficult to sample the appropriate partners.
Overall, the phase diagram shows BMP regulation allows the system to have a larger range of Wnt signals for existence of either a single crypt or multiple crypts at steady state.
Interesting questions at hand include what minimal regulatory interactions and components may give rise to spontaneous formation of multiple crypts with a periodic pattern of stem cells, TA cells, and TD cells along the crypt direction as observed in experiments?
Our computation and analysis also indicate that a loss of BMP may result in formation of more crypts (i.e. crypt multiplication) with a stable configuration; however, stronger Wnt signaling for a system without BMP may weaken such stability, leading to unbounded growth of multiple crypts as seen in experiments [ 22].
As more molecular details on Wnt and BMP in crypts are being discovered, little is still known about how complex interactions among Wnt, BMP, and different types of cells, and surrounding environments may lead to de novo formation of multiple crypts or how such interactions affect regeneration and stability of crypts.
Furthermore, starting from multiple crypts that resulted from a system with BMP and then removing BMP, we observe an "unstable progenitor pool" when Wnt regulation is strong enough.
The model presented herein has been developed mainly for studying the role of Wnt and BMP in growth of multiple crypts.
