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Preventing deformed limbs: new link found between physical forces and limb development

April 22, 2015

TORONTO, ON — Uni­ver­si­ty of Toron­to engi­neers and a pedi­atric sur­geon have joined forces to dis­cov­er that phys­i­cal forces like pres­sure and ten­sion affect the devel­op­ment of limbs in embryos—research that could some­day be used to help pre­vent birth defects.

The team, includ­ing U of T mechan­i­cal engi­neer Yu Sun (MIE), U of T bio­engi­neer Rodri­go Fer­nan­dez-Gon­za­lez (IBBME) and Sick­Kids Hospital’s Dr. Sevan Hopy­an, used live imag­ing and com­put­er mod­els to study the links between mechan­i­cal forces, changes in cell shape and cell move­ment in the embryo.

Their study—published this week in Nature Cell Biol­o­gy—uses cut­ting-edge tech­niques to gain valu­able insight into the fun­da­men­tal process­es of arm and leg devel­op­ment.

Map­ping-out the growth of ‘pro­to-limbs’

An embryo starts out shaped like a ball, then grows to cre­ate com­plex shapes like limbs. In ear­ly embry­on­ic devel­op­ment, cells divide into three lay­ers:

  • the ecto­derm, which forms the ner­vous sys­tem, skin, and sen­so­ry organs;
  • the meso­derm, which pro­duces the skele­ton, mus­cles and most of the major organs, and;
  • the endo­derm, which turns into the body’s res­pi­ra­to­ry tract and elim­i­na­tion sys­tems.

In the study, the team looked at cell behav­iours in the ecto­derm that pro­mote limb devel­op­ment. They used unique tools, includ­ing micro-chis­el­ing ablat­ing lasers, atom­ic force micro­scopes and lay­er-by-lay­er com­put­er mod­els, to explore the ear­ly stages of limbs in unprece­dent­ed detail.

They dis­cov­ered that as cells divide and devel­op, the way they com­mu­ni­cate with each oth­er and the pres­sure result­ing from move­ments of the three cell lay­ers can impact how well limb buds—the ear­ly stages of what become arms or legs—are formed.

“We found amaz­ing evi­dence on how mechan­i­cal forces reg­u­late the remod­el­ing of cells in the ecto­derm lay­er and how the stress field changes when the ecto­derm changes its shape as it devel­ops,” says Pro­fes­sor Sun.

Pri­or to this work, sci­en­tists and engi­neers did­n’t have the tools and tech­niques to under­stand changes of shapes on a tis­sue scale and on small groups of cells.

Thanks to the new study, the researchers know that two major cell lay­ers, the ecto­derm and meso­derm, speak to each oth­er both mechan­i­cal­ly and bio­chem­i­cal­ly, that is, through mol­e­cules shut­tling back and forth. This com­mu­ni­ca­tion is linked to changes in the embryo.

Engi­neer­ing insights from the world of the cell

“The idea that two tis­sues are mechan­i­cal­ly inter­act­ing and that such inter­ac­tion affects cel­lu­lar behav­iour is real­ly excit­ing to see,” says Fer­nan­dez-Gon­za­lez.

To mea­sure mechan­i­cal forces, the authors used tech­niques bor­rowed from the world of man­u­fac­tur­ing and engi­neer­ing, includ­ing cut­ting inter­faces between cells using the laser.

“If you hold a rub­ber band between your hands and I cut it while it’s loose, noth­ing hap­pens,” says Fer­nan­dez-Gon­za­lez. “But if you stretch the rub­ber band, your hands snap back when I cut it. That’s essen­tial­ly what hap­pens with cell bound­aries,” he explains.

“We know some of the genes that are impor­tant in the struc­ture of the embryo for devel­op­ment to pro­ceed, but we did­n’t know how those path­ways were linked with move­ment in the cells,” says Hopy­an.

A path to pre­vent­ing limb defects

While their study was done on a high­ly fun­da­men­tal lev­el, the team says it will allow them and oth­ers to take impor­tant fur­ther steps like mea­sur­ing forces in and between cells.

The study also paves the way for the pos­si­bil­i­ty of cre­at­ing bet­ter sim­u­la­tions of cell remod­el­ing and the ear­ly devel­op­ment of limbs.

“This research could some­day be used in poten­tial med­ical appli­ca­tions to pre­vent limb defor­ma­tions,” says Hopy­an.

The work is the first time a research team has applied bio­phys­i­cal meth­ods to the study of cell and tis­sue mechan­ics in live mam­mals.

Pos­si­ble long-term out­comes in this research field could result in a drug that could alter mechan­i­cal stress on cells in embryos, repair­ing what would oth­er­wise have become a deformed limb.


For more infor­ma­tion:
RJ Tay­lor
Media Rela­tions Strate­gist
Fac­ul­ty of Applied Sci­ence & Engi­neer­ing