Researchers here show that, in a progeroid mouse model that exhibits high levels of cellular senescence and accelerated manifestations of aging, delivering extracellular vesicles harvested from mesenchymal stem cells has much the same effect as delivering the cells as a therapy. This illustrates the point that many of these first generation approaches to stem cell therapy produce benefits via a brief period of signaling of the transplanted cells. The cells themselves die quite quickly and near entirely fail to integrate into patient tissue. Extracellular vesicles are more easily produced, stored, quality controlled, and used, overall a much better prospect from a logistical point of view. This is why there is presently such a focus on the development of therapies based on this approach.
A characteristic of aging is the loss of regenerative capacity, which leads to an impaired ability to respond to stress and therefore increased morbidity and mortality. This has led to the hypothesis that aging is partly driven by the loss of functional adult stem cells necessary for maintenance of tissue homeostasis. Indeed, mice greater than two years of age have a significant reduction in the number and proliferative capacity of various types of adult stem cells.
We previously demonstrated that muscle-derived stem/progenitor cells (MDSPC) are adversely affected upon aging. MDSPCs isolated from old and Ercc1-/∆ progeroid mice have reduced proliferative capacity and impaired differentiative potential, and this dysfunction directly contributes to age-related degeneration given that transplantation of young MDSPCs extended health span and life span in ERCC1-deficient progeroid mouse models. Transplanted MDSPCs did not differentiate or migrate from the site of injection, suggesting that the therapeutic effect of MDSPCs was mediated by secreted factors acting systemically. Concordantly, co-culture of young MDSPCs with old MDSPCs resulted in renewal of old MDSPC proliferative and differentiative potential, yet the identification of factors responsible for the rejuvenation of aged MDSPCs remained elusive.
Here, we identified bone marrow-derived mesenchymal stem cells (BM-MSCs) from young animals, and lineage-directed hESC-derived BM-MSC surrogates, as a novel source of EVs with senotherapeutic activity. We demonstrate that transplantation of BM-MSCs from young, but not old mice, prolonged life span and health span in ERCC1-deficient mice. Further, conditioned media (CM) from young BM-MSCs rescued the function of aged, senescent stem cells and senescent murine embryonic fibroblasts (MEFs) in culture.
Importantly, injection of EVs from BM-MSCs from young mice extended the life span of ERCC1-deficient mice. Similarly, treatment with EVs isolated from human embryonic stem cell-derived MSCs (hESC-MSC) was capable of significantly reducing the expression of markers of senescence in cultured senescent fibroblasts as well as naturally aged wild-type and Ercc1-/∆ mice, and improving measures of healthspan in vivo. These novel results identified EVs as key factors released by young, functional stem cells that can rescue cellular senescence and stem cell dysfunction in culture and reduce senescent cell burden in vivo. Thus, functional stem cell-derived EVs represent a novel therapeutic to reduce the senescent cell burden and extend health span.