Despite advances in cell biology, human adult cells derived from stem cells are rarely used in pharmacological and toxicological routine. Scientists from Dortmund and Cologne have explained the reason for these problems in an essay in the journal Trends in Molecular Medicine.

For example, are the differences between hepatocytes generated from stem cells and actual liver cells currently still so large that primary human hepatocytes (PHHs) obtained from liver resection currently represent the gold standard for research and toxicity tests. However, they cannot be obtained in the required quantities.

However, the development of organ cells from induced pluripotent stem cells is difficult because unwanted and incomplete cell differentiations would occur during the differentiation process. Undesired differentiated cells show properties of non-target cells (e.g. intestinal cells instead of liver cells), while incompletely differentiated cells only partially match primary cells whereas a part of the cells showed stem cell characteristics. The differentiation process of the cells is not efficient enough due to the desired degree of differentiation is often significantly below the desired value. Differentiation protocols for stem cells must therefore be optimised appropriately. Research programmes to improve the differentiation protocols are already underway.

Another point of criticism is the discrimination between toxic and non-toxic properties: Currently, in vitro systems allow to avoid unnecessary animal experiments only in cases where a theoretical therapeutic dose in human in vitro systems is already cytotoxic. The authors suggest that the performance of a test system should be better assessed using performance indicators that indicate how well a test can distinguish between toxic and non-toxic compounds.


And other important information is still missing: Many compounds cause organ toxicity through so-called primary cytotoxicity of e.g. hepatocytes or in epithelial cells of the proximal tubule of the kidney. Insufficient research has been done into the so-called secondary mechanisms triggered by compounds that cause for instance cholangiocyte toxicity in the liver. More research is needed here.

In the field of reproductive toxicity, the development of useful in vitro tests is far more complicated: For practical reasons, it is impossible to cover all facets of human embryonic and fetal development with individual assays. However, a small test battery based on signalling pathways and molecular mechanisms that control the individual development process might be sufficient. However, research into this basic question has only just begun.

The scientists have published their analysis in the journal Trends in Molecular Medicine. Agapios Sachinidis, Wiebke Albrecht, Patrick Nell, Anna Cherianidou, Nicola J. Hewitt, Karolina Edlund & Jan G. Hengstler (2019). Road Map for Development of Stem Cell-Based Alternative Test Methods. TRMOME 1439, https://doi.org/10.1016/j.molmed.2019.04.003.

For more information:
https://www.ifado.de/blog/2019/05/31/alternativen-tierversuchen-testsysteme-stammzellen/
https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30074-7