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Differentiating HSCs from Pluripotent Stem Cells: The Disrupting Role of ROS

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Review of “Reactive Oxygen Species Impair the Function of CD90+ Hematopoietic Progenitors Generated from Human Pluripotent Stem Cells” from Stem Cells by Stuart P. Atkinson

Stem cells don’t appreciate stressful situations; cell stressors lower survival, self-renewal capacity, differentiation potential, and therapeutic value. Reactive oxygen species (ROS) represent an important cell stressor known to negatively affect the self-renewal and engraftment capacity of hematopoietic stem cells (HSCs) [1, 2].

However, the importance of ROS levels to HSCs generated from human pluripotent stem cells (hPSCs) has not been fully assessed and may be of critical importance to their therapeutic value. Now, in a new Stem Cells study, the lab of Niels-Bjarne Woods (Lund University, Sweden) demonstrate that differentiation of HSCs from hPSCs generates high levels of ROS which detrimentally affects the production and function of hematopoietic cells [3]. Could this information help the lab deal with this disrupting role of ROS?

A primary assessment of the hPSC hematopoietic differentiation found supraphysiological levels of ROS and DNA damage in most hematopoietic cells when compared to cord blood cells (which express low physiological levels of ROS). Furthermore, high ROS levels led to low frequencies of more primitive hematopoietic cells, concurrent with impaired growth capacity and functional capabilities.

To deal with the disrupting role of ROS, the study employed 4 different concurrent strategies to dampen ROS production; antioxidant treatment, prevention of innate immune-cell mediated ROS release, prevention of stress-response mediated ROS generation, and reduction of oxygen tension. This reduced ROS levels by around 60% and increased the production of primitive hematopoietic progenitors from hPSCs by 22-fold. This reduction in ROS levels also afforded primitive hematopoietic progenitors with a higher proliferative capacity but, unfortunately, did not grant these cells with the capacity to engraft in transplanted NSG mice

The take home lessons from this outstanding study are clear, (1) ROS disrupt hematopoietic hPSC-differentiation from the earliest, most primitive stages, although (2) inhibition of various ROS-producing pipelines can recover some, if not all, impaired hematopoietic capabilities. 

There does, however, exist the tantalizing proposition of enhanced HSC engraftment upon a more complete inhibition of ROS to levels observed in cord blood samples. Can it be done and will it endow engraftment capabilities on hPSC-HSCs? Can ROS-reducing strategies be combined with other de-stressing strategies? 

Stay tuned to the Stem Cells and the Stem Cells Portal to find out.

References

  1. Jang YY and Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 2007;110:3056-3063.
  2. Yahata T, Takanashi T, Muguruma Y, et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 2011;118:2941-2950.
  3. Rönn RE, Guibentif C, Saxena S, et al. Reactive Oxygen Species Impair the Function of CD90+ Hematopoietic Progenitors Generated from Human Pluripotent Stem Cells. STEM CELLS 2017;35:197-206.