Immunomodulation and Regenerative Capacity of MSCs for Long-COVID

Abstract

The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments.

Clinical progress in MSC-based therapies for the management of severe COVID-19

“…For instance, prostaglandin E2 (PGE2) induces a M2 anti-inflammatory macrophage phenotype switch due to the activation of signal transducer activators of transcription-3 (STAT3) [51] . STAT3 also promotes IL-10 production, an anti-inflammatory cytokine that favors immunoregulation [52] . Likewise, IDO is another soluble factor released by MSCs.…”

“…In this regard, IL1-Ra secreted by MSCs has been proven to attenuate the antigen presenting properties of DCs [57] . Furthermore, MSC-derived EVs can contain specific microRNA (miRNA) that also contribute to the inhibition of DCs maturation [52] . Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule [58] , which is expressed as 7 different isoforms, from which HLA-G1 to G4 are membrane bound and HLA-G5 to G7 are soluble forms.…”

COVID-19 inflammation and implications in drug delivery

“…According to the stimuli received from their microenvironment, MSCs can differentiate into pro-inflammatory (MSC1) or anti-inflammatory phenotypes (MSC2). Under the COVID-19 cytokine storm, MSCs polarized to MSC2 to suppress the hyperinflammation by interacting with innate and adaptive immunity [ 5 , [168] , [169] , [170] ]. They induce the differentiation of M2 macrophages into their anti-inflammatory phenotype M1 releasing the anti-inflammatory cytokines like IL-10 and TGF- β and thereby lowering the recruitment of neutrophils [ 166 , [170] , [171] , [172] ].…”

“…The high level of cytokines in the injured site and the upregulated adhesion molecules may play a chemoattractant role in attracting MSCs to the disease area [ 166 , 170 ]. Further, surface markers such as CD44 CD29, CD18, CD24, and chemokine receptors such as CXCR4, CXCR7, and CCR2 on MSCs mediate their adhesiveness on endothelial cells expressing different ligands such as the stem cell-derived factor (SDF)-1 [ 5 , 176 ]. However, this migration is relatively low and depends on the route of administration.…”

“…The pathogenesis of the virus is mainly mediated by its envelope (E), membrane (M) and nucleocapsid (N) structural proteins, as well as its spike (S) glycoprotein facilitating its cell entry through the binding to angiotensin-converting enzyme-2 (ACE2) receptors highly expressed on pulmonary epithelial cells [ [1] , [2] , [3] , [4] ]. Although the pathogenesis of this disease is still not completely understood, growing evidence indicates that a dysregulated inflammatory syndrome is narrowly associated with COVID-19 severity and poor prognosis [ [5] , [6] , [7] , [8] ]. In some cases, the SARS-CoV-2 may induce an exaggerated immune response, resulting in an overproduction of pro-inflammatory mediators resulting in acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, and multi-organ failure [ 7 , 9 ].…”