Last month two papers created a pretty big wave in the blood stem cell field: Work from Harvard Medical School and Cornell University showed that functional human blood stem cells could be created from reprogrammed cells.
While it is most certainly the closest that researchers have come to creating blood stem cells in large numbers outside the body from using reprogramming technologies, there is still significant “T crossing and I dotting” that needs to be done; most importantly, the cells don’t quite have all the properties of their non-manipulated counterparts.
For a broad comparison of the studies and their potential implications for society, readers should check out excellent summaries by Ian Johnston at The Independent and Jessica Haemzelou at The New Scientist.
For a more research oriented summary, Carolina Guibentif and Bertie Göttgens have published a fantastic News and Views in the accompanying issue of Nature, which evaluates the common features of the studies and also comments on the theme of this blog: the importance of the cellular microenvironment for keeping stem cells “happy” outside the body.
What does this mean for stem cell scientists going forward?
First off, it is obvious from these two Nature papers (Sugimura et al. and Lis et al.) that a straightforward “reprogramming” with transcription factors is not sufficient – both procedures rely on the cells emerging from a quite specialized (and undefined!) environment of other cell types and proteins.
This indicates that researchers are really only scratching the surface of the complicated process of stem cell self-renewal, and harnessing this process for the creation and/or expansion of functional stem cells outside the body will require considerable multi-disciplinary efforts that understand the complex cellular regulators of stem cell decision making.
The papers from Sugimura and Li are a great start (and arguably the best published data to date), but the process is obviously complicated by large numbers of unknowns that result in a final cell population with some, but not all, aspects of functional human stem cells that come fresh from the body.
Secondly, we know frighteningly little about the physical properties of actual blood (or hematopoietic) stem cells (HSCs). Researchers know some things about the physical properties of mature blood cell types and mixed progenitor populations, but there are also scores of papers that tell us how different the stem cell population is – it’s very rare, metabolically quite inactive, handles genetic insults much more effectively, divides much less frequently, and lives in a highly specialized microenvironment. So, it stands to reason that these HSCs might also have different biophysical properties, but nobody really measures this….
The alarming thing is that there are numerous efforts underway in biological and chemical engineering to produce vast quantities of blood cell products for therapeutic purposes (e.g., bioreactor cultures, etc) without key information. These efforts are being undertaken with virtually no information about the most fundamental biophysical properties of the stem cell populations that are targeted for expansion and production of mature cells.
Questions as straightforward as “What happens to a blood stem cell when it is squished through a tiny space?” are fundamental to informing such scale-up efforts, yet there is surprisingly little research undertaken on the biomechanics of highly purified stem cell populations.
I predict that the next decade will be rife with such interdisciplinary efforts between stem cell biologists, physicists, chemists and engineers to try and identify the complete set of factors (inside and outside of the cell) that are required for keeping blood stem cells happy outside of the body.
The reality is that such efforts take a lot of work to get both focused research groups up to speed on the intricacies of each other’s areas of deep specialization so I hope that we continue to see significant investment in interdisciplinary collaborations and networks of scientists.
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