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Alexis Carulli CCB Project

Notch Regulation of Intestinal Crypt Dynamics. Alexis Carulli CCB Project. The Intestinal Crypt: Proliferative Zone. Transit-Amplifying Progenitor(TA). Notch?. Stem Cell. Experimental Observations. Hypothesis. Asymmetric Cell Division. 5 day Notch inhibition. 1 day Notch inhibition.

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Alexis Carulli CCB Project

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  1. Notch Regulation of Intestinal Crypt Dynamics Alexis CarulliCCB Project

  2. The Intestinal Crypt: Proliferative Zone Transit-AmplifyingProgenitor(TA) Notch? Stem Cell

  3. Experimental Observations Hypothesis Asymmetric Cell Division 5 day Notch inhibition 1 day Notch inhibition NotchInhibition Symmetric Cell Division

  4. Continuous Compartmental Model of Crypt Dynamics apoptosis apoptosis α1 β1 N0 Stem N2 Diff N1 TA differentiation differentiation sloughing-off α2 γ β2 α3 β3 renewal renewal Johnston et al. PNAS 2007 k1N21 dN2 = – γN2 + β2N1 + dt 1 + m1N1 WITH FEEDBACK: k0N20 dN0 = (α3 – α1 – α2)N0 – dt 1 + m0N0 k0N20 k1N21 dN1 + α2N0 + = (β3 – β1 – β2)N1 – dt 1 + m0N0 1 + m1N1

  5. Continuous Compartmental Model of Crypt Dynamics apoptosis apoptosis α1 β1 N0 Stem N2 Diff N1 TA differentiation differentiation sloughing-off α2 γ β2 α3 β3 renewal renewal Johnston et al. PNAS 2007 k1N21 dN2 = – γN2 + β2N1 + dt 1 + m1N1 WITH FEEDBACK: k0N20 dN0 = (α3 – α1 – α2)N0 – dt 1 + m0N0 k0N20 k1N21 dN1 + α2N0 + = (β3 – β1 – β2)N1 – dt 1 + m0N0 1 + m1N1

  6. Continuous Model: α2and α3 analysis Homeostatic rates: α2 = 0.3, α3 = 0.586 N2 1 day Notch inhibition 5 day Notch inhibition N1 N0 α2 = 1α3 = 0 α2 = 5α3 = 0.001 α2 = 3α3 = 0.586

  7. Continuous Compartmental Model of Crypt Dynamics N2 apoptosis apoptosis α1 N1 β1 N0 N0 Stem N2 Diff N1 TA differentiation differentiation sloughing-off α2 γ β2 α3 β3 renewal renewal Johnston et al. PNAS 2007 Even if N0=0 there is still a population of N1 and N2 cells:

  8. Continuous Model: β3 analysis Homeostatic rate: β3 = 0.732 1 day Notch inhibition 5 day Notch inhibition Β3 = 0 α2 = 1α3 = 0.3

  9. Discrete Compartmental Model of Crypt Dynamics ASSUMPTION: When crypt is in homeostasis, apoptosis is negligible in S and T compartments Sloughoff S Stem D Diff T1 TA T2 TA differentiation amplification differentiation γ X R renewal S(t+1) = S + (1-X)S + R X= Stem cell division symmetry X=0: completely symmetric, towards S X=1: completely asymmetric, equal S and TT X=2: completely symmetric, towards TT T1(t+1) = 3XS TT(t+1) = T1 + T2 T2(t+1) = 4T1 D(t+1)= D + 0.6T2 – γ

  10. Discrete Model: X analysis TT S S grows exponentially, TT crashes X=0 X=1 X=2 Homeostasis Maximum is 60% increased from TTi NOTE: In my experiment I saw a 60% increase in proliferating cells after 1 day of Notch inhibition

  11. Discrete Model; x=1.5 1 day Notch inhibition 5 day Notch inhibition TT S No stem cell renewal Constant stem cell renewal Notch-dependent stem cell renewal

  12. Discrete Model: Alternate hypothesis TT S Notch inhibition may result in stem cell apoptosis and the rebound stem cell overpopulation, without affecting differentiation rate of STT 1 day Notch inhibition 5 day Notch inhibition Stem cell loss Stem cell rebound

  13. Future Directions 1) Test different permutations of amplification scheme S Stem D Diff T1 TA T3 TA T4 TA T2 TA γ X R 2) Design hybrid model - Neither discrete nor continuous is likely correct - Adapt discrete model to ODEs with feedback, but maintaindependence on S compartment 3) Do more experiments! - Check intermediate time points for proliferation drop

  14. Thanks! Many thanks to the course instructors (Especially Greg!) and the TAs. It was great to meet all of you. Safe travels home and may you have many Science/Nature/Cell publications in the future 

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