Chronic inflammation is not one disease, it is the common biological driver of dozens and disorders, from autoimmune disease to cardiovascular illness; from metabolic syndrome down through neurodegenerative diseases. Here, we will look at how mesenchymal stem cell therapy targets that engine directly and what the evidence says about its modulation of immune balance, vascular health or tissue repair as well as shared points to consider for patients.
Some sicknesses do not kick in by giving you a fucking alarm bell vibe. There was no one moment, no obvious change in trajectory just a buildup of cumulative tiredness, tension and fog and discomfort in the body that creeps up so stealthily it’s as if he forgets how to feel well at all. Chronic inflammation works this way. It works quietly under the radar, eroding tissue, disrupting vascular function and immunoregulation over a period of years or decades until it produces clinically overt pathophysiological effects that can no longer be dismissed as coincidental.
There has been progress toward recognizing chronic inflammation as a key driver of disease in conventional medicine. But less successful at treating the cause as opposed to the symptoms. Anti‐inflammatory drugs will arrest flares; however rarely, if ever, normalize the underlying immune dysregulation. Bloomberg, This is exactly the gap that stem cell therapy, especially MSC (mesenchymal-derived) stem cell are garnering serious attention within research and clinical communities.
Figure 1: Chronic Inflammation and Stem Cell Therapy: Immune Balance, Circulation, and Tissue Repair
The Biology Beneath the Surface
Chronic inflammation is a very different process from acute inflammatory responses we see in wounding or fighting infections. Acute inflammation is intentional and self-containing. Chronic inflammation is neither. When the immune response cannot clear an inflammatory trigger, and so instead exists in a low-grade but damaging state of immune activation indefinitely (due to infection, metabolic stress / environmental exposure or autoimmune misfiring), that is local chronic inflammation.
Cellular machineries mediating this process consist of states with activated macrophages, aberrant T-helper cell populations and increased circulating levels of pro-inflammatory cytokines — especially TNF-α, IL1β, IL6 and CRP. They are not just markers of inflammation; they perpetuate it, destroying endothelial tissue, causing insulin resistance and activating the cellular senescence programme that hastens organ fibrosis. This cascade is no mere surface manifestation to suppress but rather the key promise of Stem cell MSC-based therapy at a mechanistic level.
How MSCs Modulate Immune Function
Bone marrow / umbilical cord tissue or adipose fat-derived mesenchymal stem cells are not actually true “stem cells” as in define that they replace damaged tissues through differentiation into replacement cell types. Their therapeutic potential is really due to what’s secreted. Stem cell MSC-based therapy mediate a wide-ranging and orchestrated immunomodulatory effect through paracrine signalling — the releasing of bioactive molecules into nearby biological surroundings.
In inflammatory environments, Stem cell MSC-based therapy increase the production of anti-inflammatory mediators such as IL-10, TGF-β and prostaglandin E2. They inhibit the expansion and activation of pro-inflammatory T-effector cells whilst enhancing proliferation regulatory T–cells (Tregs)-the immune systems natural checks on inflammation. They also modulate macrophage polarisation, converting these cells from the inflammatory M1 phenotype to an anti-inflammatory and repair-promoting M2 phenotype.
This is not immune suppression in the manner afforded by steroid therapy or biologics. Strictly defining it, though, is more like recalibration of the immune function a return to the sort of homeostasis-like immuno-regulatory balance that chronic inflammation serially disrupts.
Circulation and Vascular Repair
The coupling of chronic inflammation and vascular dysfunction suggests that exclusive interventions targeting wither process would render the clinical picture incomplete. Continuous inflammatory signalling injures develops the endothelium of blood vessels, decreases availability and production of nitric oxide that favours plaque generation atherosclerosis causing microcirculation impairment which is important to supply tissues with oxygen and nutrients.
They also incorporate Stem cell MSC-based therapy as a complementary approach to this. VEGF and HGF have angiogenic properties, they are secreted by myoblastic cells in culture, enhancing formation of capillary networks within ischaemic or poorly perfused tissue. This translates to quantifiable improvements in tissue perfusion, wound healing capacity and sometimes reduction of neuropathic symptoms amongst patients suffering from inflammatory conditions with peripheral circulation compromise.
What is unique about Stem cell MSC-based therapy compared with most pharmacological therapies is that it positions immune modulatory and vascular support at the same time in circulation, whereas few therapeutic agents will do this; they usually target either inflammation or secretion from blood cells to improve micro-vascularisation but not both.
Tissue Repair: The Third Dimension
In addition to immunomodulation and vascular support, Stem cell MSC-based therapy promote tissue repair through the production of growth factors, fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), for instance that stimulate local progenitor cells from a pool also implicated in immune responses, as well as aiding extracellular matrix remodelling. In chronic disease states, where normal repair processes are persistently disrupted, these supportive signalling may redirect the local environment from one of continuous injury towards one fostering active albeit partial healing.
What Patients Should Understand
The evidence base for Stem cell MSC-based therapy in chronic inflammation is somewhat incomplete and heterogeneous. Across conditions including rheumatoid arthritis, Crohn’s disease, systemic lupus erythematosus and chronic obstructive pulmonary disease PHASE I and II clinical trials have generally identified target-safety signals as favourable but evidence for biological activity is sparse. Definitive Phase III evidence is still sparse for most indications and there remain key questions in the field to be addressed, including optimal cell source, dosing and patient selection.
In practice, this means that contemporary Stem cell MSC-based therapy for chronic inflammation should be conceptualised as adjunctive–a rationally-structured biological complement to conventional care rather than a substitute. The optimal patients for whom benefit is the most likely occurs in those with proven inflammatory burden (led by a clinical team that deals openly and honestly not only about the promise of early data, but also the areas yet to be answered in rigorous trials).
Chronic inflammation has been characterized as the slow-burn fire smoldering underneath modern day disease. And stem cells do not put that fire out in one treatment. Yet for some patients, with the appropriate clinical rationale in mind it may be our most concerted effort to date to treat what maintains its stoking.
References
Caplan, A.I., & Correa, D. (2011). The MSC: An injury drugstore. Cell Stem Cell, 9(1), 11–15.
Dinarello, C.A. (2010). Anti-inflammatory agents: Present and future. Cell, 140(6), 935–950.
Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology, 69(Suppl 1), S4–S9.
Pers, Y.M., Rackwitz, L., Ferreira, R., et al. (2016). Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: A phase I dose-escalation trial. Stem Cells Translational Medicine, 5(7), 847–856.
Weiss, A.R.R., & Dahlke, M.H. (2019). Immunomodulation by mesenchymal stem cells (MSCs): Mechanisms of action of living, apoptotic, and dead MSCs. Frontiers in Immunology, 10, 1191.