Asymmetric cell division regulates blood stem cell fates

Blood stem cells are capable of generating both: new blood stem cells and all other blood cell types. This potential of life-long self-renewal and differentiation is not only required for a healthy blood system but is also the basis for the success of the clinical bone marrow transplantation therapy. In their recent Nature publication, scientists from the group of Timm Schroeder now prove that asymmetric cell division regulates blood stem cell fates.

09.09.2019 by Dirk Löffler and Timm Schroeder

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Cell-division_Nature2019 — When blood stem cells divide, organelles and factors associated with the cellular degradative machinery can be asymmetrically inherited by daughter cells (green: microtubuli, white: asymetrically inherited factor). Images courtesy: Florin Schneiter.

Every second, millions of new blood cells have to be generated to compensate for the constant loss of blood cells. Blood stem cells can self-renew and differentiate into all types of blood cells lifelong. How and when a stem cell decides between self-renewal and differentiation remains poorly understood. It had long been speculated that this decision could be controlled by asymmetric cell division, an evolutionary conserved mechanism used in many living creatures, from yeast to worm to fly to mammals. Here, fate decisions are made during cell division by e.g. the asymmetric inheritance of cell fate determinants. However, so far there has been no evidence that blood stem cells actually use asymmetric cell division, leaving the possibility that their fates are controlled only by mechanisms not related to cell division.

Researchers led by Timm Schroeder, a D-BSSE Professor heading the Cell Systems Dynamics group, have now investigated if the asymmetric inheritance of cell components during blood stem cell divisions affects future fates of their daughter cells. To do this, they used novel continuous single-cell imaging to quantify the behaviours of single blood stem cells and their progeny over several days.

Novel quantitative single-cell imaging

The researchers were able to identify both, factors that are asymmetrically inherited to their daughter cells during blood stem cell divisions, as well as metabolic markers that are later asymmetrically expressed in the daughter cells. Filming and tracking the cells over days allowed to demonstrate that the asymmetric inheritance of factors and organelles associated with the cellular degradative machinery can predict the future metabolic activation of the stem cell daughters. This for the first time shows that blood stem cells use asymmetric cell division as a mechanism to control future daughter cells fates.

The study answers a long-standing question and sheds new light on how blood stem cells decide their fate. This improved understanding of the molecular machinery controlling stem cells also provides novel targets for their manipulation for clinical therapy, e.g. for their improved expansion or rejuvenation.