CONCLUDING REMARKS AND FUTURE PERSPECTIVES
Finding the determinants of the aging process that help us understand age-related diseases has long been a quest by gerontologists and practitioners in the geriatric field for decades.
With emerging interests in microbiology and immunology, researchers have tried to connect and expand their knowledge to find clues to the secrets of aging and its related
dysfunction. Recently, a new paradigm of aging-related concepts termed ‘immunosenescence’ and ‘inflammation emerged, which explains the aging phenomena in terms of
immunology (6, 10, 11). Aging-dependent alterations of immune cells and the BM microenvironment lead to subclinical inflammatory states, and subsequent chronically sustained
inflammatory stimuli contribute to the functional decline of the immune system and even increased risks for leukemogenesis, supporting the inflammation concept (68). As a BM niche
factor, MSCs play a key role in modulating the immune system in the body; however, their role in the aging-immune inflammation axis remains to be elucidated. Thus, herein, we
discussed the previous reports related to the senescent MSCs and their behaviors, and propose their potential role in the progression of inflammation.
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One crucial factor for the induction and progression of inflammation is sustained stimulation of DAMP originating from senescent MSCs as their secretion of damaged macromolecules and self-debris increased with age and could lead to a subsequent spontaneous innate immune response. Age-biased bone marrow adipogenic differentiation causes not only weakened BM niche function and bone homeostasis but also dysregulates hematopoiesis, resulting in biased myelopoiesis. Inflammaging of MSCs might be involved in genomic instability of the hematopoietic system by the accumulation of recurrent ASXL1 mutations in a niche microenvironment or through mutacinogenic enzyme production. Probably the most prominent contribution of MSCs to inflammation is the mass production of pro-inflammatory cytokines during the aging process, which then further promotes M1 polarization of macrophages.
Despite present achievements in investigating the effect of MSCs on inflammation progression, there is still plenty of unexplored territory remaining to be elucidated, which includes
other mechanisms that might contribute to inflammation progression. For example, MSCs can suppress the inflammasome, which is important to their therapeutic potential against
immune-related disorders (65, 97), but the effect of senescence on the regulation of inflammasomes is less investigated.
Studies on centenarians show very different inflammation phenotypes, such as pro-inflammatory cytokine levels in plasma, even in individuals without chronic pathologies
(18); so future studies should be conducted to define features of individuals and cases (such as threshold on the stress or genotoxins), or how the inflammation-related cytokines act in
specific tissue-residing MSCs which could regulate the onset of specific chronic diseases. It also could be envisioned how inflammation contributes to changing the therapeutic efficacy of transplanted MSCs. Although some studies have reported that in vitro senescent MSCs present reduced therapeutic potentials, including immunomodulation and engraftment (98), their specific mode of action in the elderly and influences by inflammation are less investigated, regardless of whether the transplanted cells are early- or late-passaged MSCs.
Inflammation is essential for survival and has beneficial effects on harmful signal neutralization in young individuals; however, inflammation in the elderly is detrimental, and this environment possibly stimulates transplanted MSCs for further hyperactive production of SASP, followed by inhibition of regenerative or immunomodulatory ability (18). Therefore, we also need to consider the antagonistic pleiotropy of pro-inflammatory cytokines on the therapeutic mechanism of transplanted MSCs.
Lastly, most of the inflammation studies have focused on which stimuli, such as molecules and cytokines, are important for induction and progression, but, to define the relation
between inflammation and MSCs, a systemic approach to understanding the interaction of MSCs with each niche- or tissue-specific signaling cascade of receptors is needed. Our
effort to understand the complex interplay between MSCs and the aged environment and to integrate MSC therapy in the concept of inflammation will contribute to improving
preventive and personalized medicine for elderly individuals.
ACKNOWLEDGEMENTS
This work was supported by the Catholic Medical Center Research Foundation made in the program year of 2018 and the Basic Research Program (2019R1C1C1008896) through
the National Research Foundation of Korea (NRF) funded by the Korean government.
CONFLICTS OF INTEREST
The authors have no conflicting interests.
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