Cell size as driver of stem cell aging and cancer

The failure to regenerate tissue underlies a challenging health issue in elderly. A main contributor to this decline is the loss of stem cell function during aging.

Despite the essential role of stem cells, it is unclear how they fail to maintain their functions during aging and disease. I discovered a new aspect of stem cell aging in vivo: cellular enlargement. With age, stem cells increase in size leading to their functional decline. However, it is unclear how size impacts stem cell fitness.

Moreover, the physiological importance of this process remains unsolved.My team at the University of Helsinki will address these questions by: (1) identifying pathways that promote stem cell dysfunction during enlargement, (2) assessing the effects of size reduction on stem cell rejuvenation, and (3) illuminating the effects of stem cell size on cancer.Supported by preliminary data, I hypothesize that cell size is a driver of stem cell aging and cancer.

Using hematopoietic stem cells (HSCs) of mouse models, I will identify the molecular mechanisms impairing fitness of large HSCs. I will also perform a screen to identify pathways that modulate the size of HSCs to test for rejuvenation.

These will allow me to establish how HSC size affects other cellular aging pathways, organismal health and whether this relationship is causal or correlative. I hypothesize that cellular size impacts HSCs to transform into cancerous cells.

To test this, I will use differently sized, oncogenic HSCs from mice and humans to test their potential to facilitate leukemia in vivo and to investigate the underlying mechanisms of this process.The novel concepts outlined here have exceptional potential for scientific impact as they add a new paradigm to stem cell aging, provide transformative treatment perspectives and examine cancer from a new dimension.