Media Releases

Researchers discover a switch that controls stem cell pluripotency

September 15, 2011

TORONTO, ON — Sci­en­tists have found a con­trol switch that reg­u­lates stem cell “pluripo­ten­cy,” the capac­i­ty of stem cells to devel­op into any type of cell in the human body. The dis­cov­ery reveals that pluripo­ten­cy is reg­u­lat­ed by a sin­gle event in a process called alter­na­tive splic­ing.

Alter­na­tive splic­ing allows one gene to gen­er­ate many dif­fer­ent genet­ic mes­sages and pro­tein prod­ucts. The researchers found that in genet­ic mes­sages of a gene called FOXP1, the switch was active in embry­on­ic stem cells but silent in “adult” cells—those that had become the spe­cial­ized cells that com­prise organs and per­form func­tions.

“It opens the field to the fact that alter­na­tive splic­ing plays a real­ly impor­tant role in stem cell pluripo­ten­cy,” said Prof. Ben­jamin Blencowe, prin­ci­pal inves­ti­ga­tor on the study and a Pro­fes­sor in the Uni­ver­si­ty of Toronto’s Depart­ments of Mol­e­c­u­lar Genet­ics and Bant­i­ng and Best Depart­ment of Med­ical Research. “We’re begin­ning to see an entire­ly new land­scape of reg­u­la­tion, which will be cru­cial to our under­stand­ing of how to pro­duce more effec­tive pluripo­tent stem cells for ther­a­peu­tic and research appli­ca­tions.”

The find­ings were pub­lished in the cur­rent online edi­tion of the sci­en­tif­ic jour­nal Cell.

Alter­na­tive splic­ing works by allow­ing dif­fer­ent seg­ments of genet­ic mes­sages, also known as mes­sen­ger RNAs, to be spliced in dif­fer­ent com­bi­na­tions as the mes­sages are copied from a gene’s DNA. Those com­bi­na­tions make dif­fer­ent mes­sen­ger RNAs, which in turn become dif­fer­ent pro­teins.

In stem cells, sci­en­tists have shown that a core set of pro­teins called tran­scrip­tion fac­tors con­trol pluripo­ten­cy.

The splic­ing event dis­cov­ered by Blencowe’s team, includ­ing first author on the study Dr. Math­ieu Gabut, changes the DNA bind­ing prop­er­ties of FOXP1 in a way that then con­trols the expres­sion of the core pluripo­ten­cy tran­scrip­tion fac­tors, to facil­i­tate main­te­nance of pluripo­ten­cy. “As a mech­a­nism that con­trols those core tran­scrip­tion fac­tors, it’s right at the heart of the reg­u­la­to­ry process of pluripo­ten­cy,” said Blencowe.

At the same time, the mech­a­nism repress­es the genes required for differentiation—the process where­by by a stem cell los­es “stem­ness” and becomes a spe­cif­ic cell type that makes up an organ or per­forms a func­tion.

As well, in col­lab­o­ra­tion with col­leagues includ­ing Profs. Jeff Wrana and Andras Nagy in the Samuel Lunen­feld Research Insti­tute at Mount Sinai Hos­pi­tal, also Pro­fes­sors in U of T’s Depart­ment of Mol­e­c­u­lar Genet­ics, the splic­ing switch iden­ti­fied by Blencowe’s team was shown to play a role in “repro­gram­ming,” a poten­tial­ly ther­a­peu­tic tech­nique in which researchers coax adult cells back into induced pluripo­tent stem cells by intro­duc­ing the core tran­scrip­tion fac­tors. “That’s an impor­tant area in the field where we need bet­ter under­stand­ing because repro­gram­ming, espe­cial­ly with human cells, is very inef­fi­cient,” said Blencowe. “Often when repro­grammed stem cells are not ful­ly repro­grammed they become tumori­genic and can lead to can­cer.”

Poten­tial appli­ca­tions for stem-cell sci­ence include grow­ing cells and tis­sues to test new drugs or to repair or replace dam­aged tis­sues in many dis­eases and con­di­tions, includ­ing heart dis­ease, dia­betes, spinal cord injury and Alzheimer’s dis­ease.

As well, a bet­ter under­stand­ing of the mech­a­nisms that reg­u­late pluripo­ten­cy, cell divi­sion and dif­fer­en­ti­a­tion will pro­vide knowl­edge of how dis­eases like can­cer arise and sug­gest more tar­get­ed ther­a­peu­tic approach­es.

Blencowe and his lab have recent­ly turned their atten­tion to what might be con­trol­ling the fac­tors that con­trol both alter­na­tive splic­ing and the main­te­nance of stem-cell pluripo­ten­cy. They have, said Blencowe, a few tan­ta­liz­ing glimpses. “There’s still a lot to fig­ure out, but I per­son­al­ly believe there is huge poten­tial in the future. If we can ful­ly under­stand the reg­u­la­to­ry con­trols that allow us to make uni­form pop­u­la­tions of ful­ly repro­grammed stem cells, there’s no rea­son why they shouldn’t be effec­tive for many dif­fer­ent ther­a­pies. It will come.”

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Fund­ing for the study was pro­vid­ed by the C.H. Best Foun­da­tion, the Cana­di­an Can­cer Soci­ety, the Cana­di­an Insti­tutes of Health Research, Genome Cana­da through the Ontario Genomics Insti­tute, the Nation­al Insti­tutes of Health, the Ontario Min­istry of Research and Inno­va­tion, and the Ontario Research Fund.

 

Oth­er co-authors on the study: Pay­man Samavarchi-Tehrani (Cen­tre for Sys­tems Biol­o­gy, Samuel Lunen­feld Research Insti­tute, and Dept. of Mol­e­c­u­lar Genet­ics, U of T); Xinchen Wang, Valenti­na Slo­bo­de­ni­uc, Dave O’Hanlon, Sha­heynoor Talukder, Qun Pan, and Tim­o­thy Hugh­es (Bant­i­ng and Best Dept. of Med­ical Research, U of T, and The Don­nel­ly Cen­tre for Cel­lu­lar and Bio­mol­e­c­u­lar Research, U of T); Hoon-Ki Sung and Knut Wolt­jen (Cen­tre for Stem Cells and Tis­sue Engi­neer­ing, SLRI); Manuel Alvarez (The Don­nel­ly Cen­tre, and the Insti­tute of Bio­ma­te­ri­als and Bio­med­ical Engi­neer­ing, U of T); Este­ban Maz­zoni, Stephane Ned­elec and Hynek Wichter­le (Colum­bia Uni­ver­si­ty Med­ical Cen­ter); Peter Zand­stra (The Don­nel­ly Cen­tre and IBBE).

 

For more infor­ma­tion, please con­tact:

Jim Old­field
Uni­ver­si­ty of Toron­to Temer­ty Temer­ty Fac­ul­ty of Med­i­cine
416–946-8423
jim.oldfield@utoronto.ca
www.facmed.utoronto.ca
http://twitter.com/#!/uoftmedicine