First generation mesenchymal stem cell therapies have been shown over the years to fairly reliably suppress chronic inflammation for some time, whether disease-associated or aging-associated. The transplanted cells die quickly, but the effects of their brief burst of signaling can last for months. Other intended benefits, such as increased regeneration or function, are in comparison unreliable at best. In part the challenge is that there is no standard in this part of the field, every clinic uses different methodologies and cell sources. These differences appear to matter greatly, and the fine details of why they matter greatly remain poorly cataloged and poorly understood.
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can be isolated from the bone marrow, adipose tissue, dental tissues, skin, salivary gland, limb buds, menstrual blood, and perinatal tissues. Although MSCs do not differentiate into immune cells, MSCs provide a supporting microenvironmental niche for hematopoietic stem cells (HSCs) to differentiate into myeloid and lymphoid cells, which are essentially the immune cells. One of the speculated theories of declining immunity as the host ages is the MSC senescence. Subsequently, the functions and structures of MSCs, which are significant in maintaining the immune system, diminishes.
Numerous studies have proven that MSCs have low immunogenicity, excellent immunomodulatory function, and homing capability to regenerate damaged tissues through multipotent differentiation and paracrine secretion. Despite that, current studies are not primarily focused on aging or the restoration of the immune system. There have been extensive studies conducted on pathological conditions than actual aging itself. Aging and MSC were studied separately, but the similarities of the immune markers involved may come into convergence. The proliferative capacity and immunomodulatory function of MSCs could aid in the restoration of the immune cells and reduce the pro-inflammatory markers since these parameters are observed in aging as well. MSCs might not be a permanent solution to restore a healthy cell population, however. MSCs may have been seen as effective in past studies due to their paracrine effects but not cell replacement. This may explain the relatively fast drop in the inflammatory state when MSC therapy commences.
Some evidence shows that the ameliorating effects of MSCs on the immune system are not due to direct engraftment and cell replacement, but rather paracrine manner and direct cell-to-cell contact. MSCs secrete soluble paracrine factors and express IL-10, which is an anti-inflammatory and immunoregulatory cytokine. Furthermore, they produce IL-6 and IL-8, which are known to be associated with MSC tissue repair potential. Subsequently, MSCs control the inflammatory state as evidence of the reduced expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and CRP. Moreover, MSC-secreted TGF-β has a role in macrophage polarization towards the M2 phenotype. These M2 macrophages stimulate the expression of IL-10, which alleviates inflammation. The mechanism of action of MSCs on the immune system is not constitutively inhibitory, but is acquired after exposure to the inflammatory environment with IFN-γ. IFN-γ is one of the cytokines released by T cytotoxic cells during inflammation. Therefore, in Th17 centered inflammatory response, MSC treatment would require the addition of regulatory T cells to successfully regulate the inflammation.
Immunosenescence is an inevitable phenomenon that involves the remodeling of the immune system with age. This complex interaction between the age-accumulated insults, aged HSCs bias to myeloid cells, and both the innate and adaptive immune system results in a chronic, subclinical systemic inflammation termed as 'inflammaging'. The individuals over 65 years old have increased risk of infection, cancer, higher morbidity, and mortality of disease, and reduced vaccine efficacy. Currently, there are no effective countermeasures available to ameliorate immunosenescence. MSC therapy is a promising modality to rejuvenate the aged immune system. As of now, studies have shown that MSCs can safely reduce the inflammatory markers, restore the T cell repertoire, and improve the histopathology of inflammatory disease.