Mesenchymal stem cell (MSC) therapies as presently practiced, even given considerable differences in what exactly is meant by "mesenchymal stem cell", fairly reliably reduce the chronic inflammation of aging for an extended period of time. They are much less reliable at inducing regeneration of tissues, and where that does occur it probably results from dampened inflammation. One of the many detrimental consequences of the always-on inflammatory signaling that arises with age is a disruption of regenerative capacity. Given the ability of MSC transplantation to suppress inflammation, it is possible that this could be at least marginally useful as a therapy for any age-related condition in which inflammation is an important component.

Here, researchers consider MSC therapies as a way to slow down atherosclerosis, as inflammation strongly influences the pace at which this condition progresses. They also suggest that atherosclerosis is linked to the age-related failure of native MSCs to regulate inflammation. There are several possible reasons for this. Firstly, inflammation goes hand in hand with oxidative stress, the presence of greater levels of oxidizing molecules. This means it also leads to more of the oxidized lipids that cause macrophages attempting to clean up atherosclerotic lesions to become harmful foam cells that instead accelerate growth of the lesions. Secondly, macrophage behavior is influenced by the state of inflammatory signaling. Macrophages that are normally helpful can be coerced into amplifying inflammation, switching to an aggressive inflammatory mode rather than assisting in repair of lesions.

Atherosclerosis, a chronic inflammatory disease of the wall of large- and medium-sized arteries, is the most common pathological process leading to cardiovascular disease (CVD). The hallmark lesion in atherosclerosis is the atherosclerotic plaque. An alternative strategy to target inflammatory pathways for CVD therapy could be enhancing physiological mechanisms that antagonize inflammation. Key cellular targets for this approach are multipotent mesenchymal stromal cells (MSC). MSC are non-hematopoietic clonogenic perivascular multipotent stromal cells that can be induced to differentiate in vitro into osteoblasts, chrondrocytes, or adipocytes. MSC function as pivotal regulators of inflammation by modulating innate and adaptive immune cells. This does not require long-term engraftment of MSC in target tissues. The crosstalk between MSC and immune cells is mainly mediated by secreted bioactive molecules.

Limited data are available for MSC from patients with atherosclerosis. Specifically, the contribution of MSC dysfunction to the persistence of chronic inflammation and plaque progression are ill-defined. This relates in part to the lack of specific markers that can identify MSC in vivo in human arteries. We have overcome this obstacle by using an alternative approach. Thus, we have characterized adipose derived MSC from atherosclerotic patients (i.e. subjects undergoing coronary artery bypass graft surgery) and compared their function with MSC from non-atherosclerotic patients. Immunopotency (i.e. the MSC capacity to suppress the proliferation of allogenic activated T-cells) was used as the main readout of MSC function. Initial findings confirmed that atherosclerotic-MSC have impaired immunomodulatory capacity and a pro-inflammatory secretome, both contribute to the state of chronic low-grade inflammation that promotes atherosclerosis progression. Moreover, we demonstrated that MSC immunopotency can indeed be enhanced by modulating inflammatory components of the MSC secretome.

There are multiple potential implications of these data. First, the therapeutic effectiveness of atherosclerotic-MSC is likely compromised when compared to their non-atherosclerotic counterparts. Accordingly, only non-atherosclerotic MSC should be used in clinical trials. Second, the ability to modulate the redox state of MSC is a possible strategy to enhance the therapeutic efficacy of autologous atherosclerotic-MSCs. Third, increasing age is an established independent risk factor for the development of atherosclerosis. Notably, mitochondrial dysfunction is not only associated with aging, but also with premature or accelerated atherosclerosis. Our study was not designed to examine the contribution of MSC dysfunction to atherosclerosis onset or progression. However, our results strongly suggest this link, and we have set the stage to test this hypothesis in the future.