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The many dimensions of stem cell biology



Before the renaissance it was thought that the world was flat, and woe betide anyone who said differently! Things are not quite so bad these days, but not so long ago the stem cell world had a tendency to be flat too.  The vast majority of stem cell cultures were 2-dimensional. Cells are much easier to grow on a “flat” surface and it’s easier to control the type of surface you want them to attach to. Getting growth factors, nutrients, and oxygen to the cells is straightforward, and if some of them die they’ll probably just float away and you can get rid of them at the next medium change. The problem is that people, mice, plants, etc. are not flat. They are all composed of intricately constructed structures that rely upon 3-dimensional interactions of cells occupying relatively fixed positions within a scaffold of extra-cellular matrix. 

Tissue-specific stem cells are a prime example of this reliance. The “niche” or microenvironment that supports diverse types of stem cells works because the stem cell is able to make contact with other types of somatic cells that surround the stem cell on all of its surface.  Loss of contact with even one of the somatic cells increases the probability that the stem cell will differentiate or die.  Perhaps our brains are an even better example.  Neural functions seem to rely upon complex sets of connections between individual neurons and it is difficult to imagine how all these links could be constructed between neurons in a flat cell monolayer – even integrated circuits are now progressing towards 3D and they are still poor mimics of the brain’s capacity for data processing.

So, in view of these limitations of “flat” cultures, it is no surprise that a number of stem cell researchers are moving towards 3D systems to differentiate pluripotent stem cells (PSCs) into interesting structures that might be better mimics of in vivo organ physiology. These systems may be better tools not only to increase our understanding of how organs develop in utero, but also how they respond to small molecules identified as potential drugs.  Six hours before this blog was written, Medical News Today reported the publication of a study by James Wells and Michael Helmrath describing the creation of 3D gastric organoids from human PSCs. This follows the group’s publication earlier this month of an in vivo model of the human small intestine generated by inducing PSCs towards definitive endoderm, pushing them down a hindgut development path, then implanting the resulting structures under a mouse kidney capsule for 6 weeks to complete their development (see Nature Medicine 2014 Oct 19. doi: 10.1038/nm.3737. [Epub ahead of print] for details).  But Helmrath et al. are not alone in this endeavour. Hans Clevers of the Hubrecht Institute in the Netherlands has been trying to understand intestine development for some time and his group has also published on the subject of 3D organoids, focussing on the culture of gastric stem cells extracted from healthy digestive tracts. 

The list goes on!  Researchers have created kidney organoids, tissues that mimic the branching of epithelia in the mammary gland, liver type structures, and more. The most impressive of these investigations generate structures with a high degree of similarity (at least from the morphological point of view) to their ex vivo counterparts in a developing embryo and all achieved without the somewhat messy business of transplanting the developing chunk of tissue under a kidney capsule. A couple of years ago, Yoshiki Sasai demonstrated the self-assembly of optic cups with stratified retinal structures simply by differentiating mouse embryonic stem cells in the presence of a tightly controlled regime of growth factors (Cell Stem Cell. 2012 Jun 14; 10(6):771-85) and this was followed in 2013 by work from Eri Hashino showing that a similar trick could be achieved to make inner ear sensory epithelia (Nature. 2013 Aug 8; 500(7461):217-21). Last year, Juergen Knoblich’s lab published a protocol for making 3D brain organoids from PSCs – their so-called cerebral organoids. (Nature. 2013 Sep 19; 501(7467):373-9) These structures demonstrated discrete, interdependent regions (such as a cerebral cortex-like area) and were thought to recapitulate human cortical development which, for such a complex tissue, is quite remarkable. 

So, if you’re sick of stem cells that won’t differentiate the way you want or your cells produce “hard to explain” data, don’t despair! The future’s not flat, it’s 3D!

-Dr. Lyle Armstrong