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3D human tissue culture: modeling environmental effects on the stem cell epigenome

Epigenomics Commentary on the succeptibility of stem cells’ epigenomes to be altered by the culture environment, by Justin A Colacino from University of Michigan School of Public Health (Ann Arbor, MI, USA).

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Nov 28, 2016

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Go to the profile of James L. Sherley, M.D., Ph.D.

"Regarding 3-dimensional spheroid-based stem cell research and applications: Has experimental convenience caused the need for continued validation testing to be obscured and abandoned?'

The review and perspective presented by Colacino and colleagues exemplifies a silent killer logic in the field of stem cell biology that may ultimately undermine the advance of sound knowledge on the functioning of stem cells in tissues in vivo.

There are many studies over many years to support the idea of the importance of cell-cell and cell-ECM interactions in the development and function of tissue stem cells. And there is no doubt that the explant of tissue stem cells into simple 2-dimensional culture systems disrupts these important interactions and functional relationships. The perspective from Colacino and others cites studies that show, clearly, that the molecular and cellular properties of stem cells (though more likely committed progenitor cells) differ depending on whether they are maintained in 2-dimensional culture systems or 3-dimensional systems like spheroids. The silent killer logic, rarely addressed explicitly, is the conjecture that 3-dimensional spheroid culture systems, which restore some features of cell-cell and cell-ECM interactions, therefore, necessarily restore important elements of normal stem cell function and regulation in tissues.

Over the years, this idea has been elevated gradually from hypothesis to theory and onward to now generally accepted dogma. Biological research on the topic has moved on to engineering applications without actual validation of the central hypothesis, that not only does spheroid culture change the properties of "stem cells" compared to 2-dimensional cultures, but it also recapitulates essential properties of stem cells in tissues in vivo. Now, spheroid culture can certainly regain several features of in vivo tissues (e.g., cell polarization). However, compared to intact tissue units, they have many types of disorganization and disorder in cellularity, cell kinetics, and cell regulation. How well do they model tissues in vivo and how will their shortcomings impact their use for discovery and biomedical applications? These are not criticisms. They are critical assessments that are essential for establishing the best science and the best application of these experimental models. Glossing over these issues compromises the utility of these experimental models for stem cell research and stem cell medicine. The now common application of the term "organoid" for the previous "spheroid" terminology, which was less prejudicing , is indicative of the present situation.

The present criticism is not given to suggest that the current state of research and development practice for 3-dimensional tissue stem cell research and development will prevent achievement of efficacious knowledge and new medical therapies. Instead, it is given to suggest that these goals would be achieved sooner, if the convenience of using spheroids as models for stem cell function were better matched with more extensive in vivo validation studies by many different academic labs and companies. Of course, such in vivo validation studies are not very convenient to conduct at all!

James L. Sherley, M.D., Ph.D.
Asymmetrex, LLC