report on mathematical approaches to stem cell pluripotency

8/17/2019 Report on Mathematical Approaches to Stem Cell Pluripotency

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Mathematical Approach

to Modeling Developmeand Reprogramming

Rob Morris a,1

, Ignacio Sancho-Martinez b,1

, Tatyana O SharpeCarlos Izpisua Belmonte b,!a Computational Neurobiology Laboratory and b Gene Expression L

Salk Institute for Biological Studies, La Jolla, C !"#$%

"#blication Details$ PNAS, Volume 111 No. 14, April 8 2014. “&ttp'(()))*pnas*org(content(+++


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Mathematical Approaches to Modelin !e"elopment and

Some De%nitions$

• Stem cell $ has the a%ilit& to 'orm all adult c

• i"S& 'induced pluripotent stem cells() reproraadult cells to %ecome em%r&onic stem cell

• Transcription *actors) acti"ates e(pression o' manenes

• '&ell( Di+erentiation ) the process 'rom stem cell tcell


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O#tline$

I De%ne some biological terms

II addington .andscape ) a representato* cell di+erentiation

III&ite res#lts *orm recent /or0s

IMathematical approaches to cellreprogramming

&oncl#sions and a#thors2 perspective



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4rom the Abstract

i)*ere +e discuss recent ad"ancements in iPS reproraintroduce mathematical approaches to help map reproram


ii) -ur modeliation indicates that -S/M/t&e 0amanaka factors 3lf, c14yc5 e(pression diminishes andor chanes potential %arrcell states and epienetic remodelin 'acilitate these transitions.

iii) he modelin approaches predict the time necessar& i"en num%er o' iPS colonies.


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addington .andscape

pl#ripotency

Di+erentiated cells

1 T/o types o* baa 6et/een the pl#

and di+erentiateb 6et/een di+eren

3 .ac0 rigoro#s 7

5 The comple8ities o* molered#ced into an e+ective

! Top ) to ) bottom $ di

a 9at#rally occb *avo#red me

6ottom-to-top$ da 9eeds energy e8p

b Removal o* “mole



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Reprogramming;Dedi+erentiation is possible thro#

1. Additional e(pression o' the amana3a 'actotranscription 'actors)

2. 5se o' other transcription 'actors

6. 5se o' chemicals

4. !irect modi7cation o' epienetic components



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T/o 7#estions that arose /ithdedi+erentiation$

1. s dedi9e'or some ecells onl&:

2. s dedi9erentipath sadi9erentiati



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&ited /or0$

1. 5sin statistical phnone;uili%rium net+or3 ciet al. +ere a%le to ma

segment o* the landscape.

2. A multipotent cell stmetasta%le state and >o/o* the attractor basins.

6. he& o%ser"ed a hyster he most pro%a%le di9ere+as not e;ual to the modedi9erentiation path.

i) chance 'or di9erentiation is lare +ith %ier a, smaller +hen it alr

5

(

a



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3 models o* progressing to a pl#ripotent state d#ring dirreprogramming

*anna D, et al. 200E) !irect cell reprorammin is a stochastic process amena%le to acceleration. N

!eterminist

ic


Stochastic


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*anna D, et al. 200E) !irect cell reprorammin is a stochastic process amena%le to acceleration.

Res#lts

P F umulati"e p

N/t5 F num%er o'

3 F cellintrinsic r

6 F population re

ell population d&namic

& # m # l a t i v e

" r o b


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&omparison o* analytic %ts

Grom *ana et al.


,

u m u l a t i " e P r o % .

umulati"e Pro%)

Pro%a%ilit&)

Dashed intermedmodel met al , t&i

t&e main Solid lidri'tdi9usolution Planc3 e;

#ai, et al. 2016) !eterministic direct reprorammin o' somatic cells to pluripotenc&. Natu


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Go33er Planc3 e;uation


n statistical mechanics, 4o00er-"lanc0 e7#ationdi9erential e;uation that descri%es the time e"olution o' 'unction o' the "elocit& o' a particle under the inHuence

and random 'orces.n this paper, the authors used the Go33erPlanc3 'ormalism to in'er the shape o' ane9ecti"e potential o"ernin thereprorammin process to 7t the distri%ution'or the e(periments.

he %est 7t 'or the e(perimental data is a Hatlandscape +ith a shallo+ slope.

Time '/ee0s(

B i "

S & s

A$

6$

&$

D$


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Se7#ential %t /ith s#bsets o* data


Grom le't to riht, +e increase the n#mber o* data points that are #sed to %t thmodel to the measurements. !ata points omitted 'rom the 7t are sho+n in ra&I dsho+ the 7t usin all time points. J9ecti"el&, one the pea3 in the reprorammin rao%ser"ed, ne can ma3e accurate predictions 'or the 'uture time course o' the repro


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&oncl#sions and "erspectives

• All cells ha"e the potential 'or reprorammin.

• Accordin to dri'tdi9usion model, the %arriers disaHattenin or %ein e9ecti"el& modi7ed durin the p

• he dri'tdi9usion model doesnKt re;uire a priori 3o' the ene circuitr& and reduces the hihdipro%lem to a sinle dimensional e9ecti"e potential.

• Models could allo+ or the prediction o' entire distrireprorammin times +ith Lust a 'e+ initial data poi



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- Cnd -

Thank you for listening.


report on mathematical approaches to stem cell pluripotency

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