Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate

Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization that individual HSCs might be preset differentially already from young age, HSCs might also age asynchronously. Evaluating the prospects for HSC rejuvenation therefore ultimately requires approaching those HSCs that are functionally affected by age. Here we combine genetic barcoding of aged murine HSCs with the generation of induced pluripotent stem (iPS) cells. This allows us to specifically focus on aged HSCs presenting with a pronounced lineage skewing, a hallmark of HSC ageing. Functional and molecular evaluations reveal haematopoiesis from these iPS clones to be indistinguishable from that associating with young mice. Our data thereby provide direct support to the notion that several key functional attributes of HSC ageing can be reversed. Age-associated decline in tissue function has been linked to alterations in adult stem cells, with implications for organ homeostasis and cellular therapy. Here, the authors study the heterogeneity of ageing mouse haematopoietic stem cells (HSCs) and find that the compromised blood cell-forming potential of individual and functionally defined aged HSCs can be reset by reprogramming.