Capybara: A computational tool to measure cell identity and fate transitions

Profiling intermediate cell states in high resolution

“…Using a method for transition scoring based on the proximity of cells to hybrid states, Capybara identifies higher transition rates in the first two days of reprogramming than at the initial or the final time points. Furthermore, Kong et al (2022) show that these transition scores are correlated with graph connectivity and RNA velocity, lending support to the notion that they capture local changes in cell state space. It would also be of interest to compare the transition scores as defined here with those based upon entropy and concepts from statistical physics ( Teschendorff and Feinberg, 2021 ).…”

“…Capybara ( Kong et al., 2022 ) is a new tool to ID cells, a giant rodent bouncer, if you will. Established methods are able to identify cell fates when these are well-defined states, such as previously known cell types ( Herman et al., 2018 ; Setty et al., 2019 ); the task becomes more difficult when cells acquire less well-characterized cell states.…”

“…In many cases it has transpired that the more data we gather, the less we know with certitude. Kong et al. (2022) offer new means to work with this uncertainty rather than fight against it.…”

Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

“…In agreement with our previous reports, using a healthy and regenerating liver atlas, iEPs generated with Hnf4-Foxa1 alone classify mainly as stromal cells (Figure 5G). However, following the addition of Fos and Yap1, a significant population (p<0.0001, randomized test) of injured BECs emerges, in similar proportions as observed in long-term cultured iEPs (Kong et al, 2022). In addition to several hybrid cell types that we previously reported, we also observe a significant expansion of a normal BEC population, from ~4% to ~12-35%, particularly upon the addition of Yap1 to the reprogramming cocktail (p<0.0001, randomized test), where endogenous Fos expression is also upregulated (Figure S5G).…”

“…However, we demonstrated that these cells also harbor intestinal identity and can functionally engraft the colon in a mouse model of acute colitis, prompting their re-designation as iEPs (Guo et al, 2019;Morris et al, 2014). More recently, we have shown that iEPs transcriptionally resemble injured biliary epithelial cells (BECs) and exhibit BEC-like behavior in 3D-culture models (Kong et al, 2022). Building on these studies, our single-cell lineage tracing of this protocol revealed two distinct trajectories arising during MEF to iEP conversion: one to a successfully reprogrammed state, and one to a dead-end state, where cells fail to fully convert to iEPs (Biddy et al, 2018).…”