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Alexis Carulli CCB Project Notch Regulation of Intestinal Crypt Dynamics

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The Intestinal Crypt: Proliferative Zone Transit-Amplifying Progenitor(TA) Stem Cell Notch?

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Experimental ObservationsHypothesis Asymmetric Cell Division Symmetric Cell Division Notch Inhibition 5 day Notch inhibition 1 day Notch inhibition

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Continuous Compartmental Model of Crypt Dynamics α1α1 α2α2 α3α3 β1β1 β2β2 β3β3 γ apoptosis renewal differentiation sloughing-off N 0 Stem N 1 TA N 2 Diff WITH FEEDBACK: = (α 3 – α 1 – α 2 )N 0 – k 0 N 2 0 1 + m 0 N 0 dN 0 dt k 0 N 2 0 1 + m 0 N 0 = (β 3 – β 1 – β 2 )N 1 – k 1 N 2 1 1 + m 1 N 1 dN 1 dt + α 2 N 0 + = – γN 2 + β 2 N 1 + k 1 N 2 1 1 + m 1 N 1 dN 2 dt Johnston et al. PNAS 2007

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Continuous Compartmental Model of Crypt Dynamics α1α1 α2α2 α3α3 β1β1 β2β2 β3β3 γ apoptosis renewal differentiation sloughing-off N 0 Stem N 1 TA N 2 Diff WITH FEEDBACK: = (α 3 – α 1 – α 2 )N 0 – k 0 N 2 0 1 + m 0 N 0 dN 0 dt k 0 N 2 0 1 + m 0 N 0 = (β 3 – β 1 – β 2 )N 1 – k 1 N 2 1 1 + m 1 N 1 dN 1 dt + α 2 N 0 + = – γN 2 + β 2 N 1 + k 1 N 2 1 1 + m 1 N 1 dN 2 dt Johnston et al. PNAS 2007

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Continuous Model: α 2 and α 3 analysis 1 day Notch inhibition5 day Notch inhibition α 2 = 1 α 3 = 0 α 2 = 3 α 3 = 0.586 Homeostatic rates: α 2 = 0.3, α 3 = 0.586 α 2 = 5 α 3 = 0.001 N2N2 N0N0 N1N1

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Continuous Compartmental Model of Crypt Dynamics α1α1 α2α2 α3α3 β1β1 β2β2 β3β3 γ apoptosis renewal differentiation sloughing-off N 0 Stem N 1 TA N 2 Diff Even if N 0 =0 there is still a population of N 1 and N 2 cells: Johnston et al. PNAS 2007 N2N2 N0N0 N1N1

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Continuous Model: β 3 analysis Homeostatic rate: β 3 = 0.732 1 day Notch inhibition5 day Notch inhibition Β 3 = 0 α 2 = 1 α 3 = 0.3

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D (t+1) = D + 0.6T 2 – γ T1 (t+1) = 3XSTT (t+1) = T 1 + T 2 T2 (t+1) = 4T 1 S (t+1) = S + (1-X)S + R Discrete Compartmental Model of Crypt Dynamics X R γ ASSUMPTION: When crypt is in homeostasis, apoptosis is negligible in S and T compartments renewal differentiation amplification Slough off S Stem T 1 TA D Diff T 2 TA differentiation 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

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

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Discrete Model; x=1.5 1 day Notch inhibition5 day Notch inhibition No stem cell renewal Constant stem cell renewal Notch- dependent stem cell renewal TT S

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Discrete Model: Alternate hypothesis 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 TT S Stem cell loss Stem cell rebound

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Future Directions X R γ S Stem T 1 TA D Diff T 2 TA T 3 TA T 4 TA 1) Test different permutations of amplification scheme 2) Design hybrid model - Neither discrete nor continuous is likely correct - Adapt discrete model to ODEs with feedback, but maintain dependence on S compartment 3) Do more experiments! - Check intermediate time points for proliferation drop

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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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