Researchers here report that transplanting bone marrow from young donor mice into old recipient mice produces a range of benefits, such as improvement in the behavior of macrophage cells. Bone marrow stem cells are responsible for producing blood and immune cells, among other important populations, and this capability is degraded in a number of ways with age. Introducing younger stem cells and their supporting structures is a plausible means to at least partially reverse this process. That said, this sort of approach is unlikely to arrive in human medicine in exactly the same form, given the challenges involved in bone marrow transplantation. It is not a procedure one would want to undergo unless there were no other options, and deploying it widely as a preventative therapy doesn't seem feasible in the present environment. The more likely outcome is for researchers to continue to work in mice so as to better identify specific mechanisms involved in bone marrow aging, those that might be manipulated with small molecule drugs, gene therapies, and the like.
The bone marrow is an important reservoir of stem cells and progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immunosenescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury. The bone marrow is also an important source of endothelial progenitor cells (EPCs) which participate in the generation and repair of vasculature endothelium; aging leads to a decline in circulating EPC number and function.
Different strategies have been proposed to rejuvenate the aged bone marrow such as pharmacological treatments, gene therapy, and dietary interventions. However, most approaches have focused on the effect of rejuvenation on HSC differentiation and EPC colony formation rather than effects on peripheral tissues. Therefore, we hypothesized that reconstituting aged mice with young bone marrow leads to stable engraftment of young cells in aged mice and rejuvenates tissue repair responses.
We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction. Aged mice were reconstituted with young Sca-1+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells, increases epicardial derived cell migration/activation, and enhances the acute inflammatory response following myocardial infarction in aged mice.
Beyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia. Within the retina these cells secrete cytoprotective factors such as fibroblast growth factor-2 and insulin-like growth factor-1 which limit cell death following ischemia/reperfusion injury. More recently, we also demonstrated that bone marrow rejuvenation leads to the introduction of young bone marrow-derived microglia in the brain and that these cells act to improve learning and memory responses compared with mice receiving old bone marrow. Mechanistically, young bone marrow-derived microglia adopt a neutral or anti-inflammatory phenotype while old bone marrow-derived microglia adopt a pro-inflammatory phenotype. These results are consistent with studies which have linked increased neuroinflammation to a decline in cognitive function.