Partial reprogramming for hematopoietic system rejuvenation: Impact on systemic hallmarks of aging and health span

forthcoming

Aging is a complex process, encompassing the decline numerous cell types and organs. In this regard, recent progress suggests that the hematopoietic system is particularly influential; as we age, hematopoietic stem cells (HSCs) preferentially differentiate toward the myeloid lineage, thus losing their ability to regenerate fully functional blood tissue. Furthermore, a decline in the effector capacity of immune cells accounts for insufficient immunosurveillance of senescent cells, leading to their accumulation throughout the body. From a therapeutic perspective, the hematopoietic system is particularly malleable to rejuvenating interventions. In recent years, strategies of epigenetic reprogramming achieved through the transient expression of the Yamanaka factors Oct4-Sox2-Klf4 (OSK) and the facultative expression of c-Myc -referred to as partial reprogramming- has progressively garnered attention for its potential application in regenerative medicine. Their capacity to transiently push fate-committed cells back to their developmental program and to remove epigenetic marks of damage enhances the capacity of tissues to regenerate after injury in several preclinical models. However, it is poorly understood whether single-organ partial reprogramming affects other tissues and health span, without risks for secondary transformation, undermining the translational potential for humans. Across the REJUVIMMUNE project, I leverage on these limitations to develop unique tools –mRNA therapeutics and partial reprogramming mimicking cocktails (PRMCs)– for targeting partial reprogramming on HSCs (Objective 1) and elucidate cell intrinsic and extrinsic effects of OSK-rejuvenation on blood cells -including immune cells- and systemic aging, respectively (Objective 2). In summary, the strategies proposed in this action hold great potential to counteract hematopoietic senescence and mitigating age-associated decline in organismal function, enhancing health span and organismal resilience.