Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Abstract

Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo, thus they may efficiently target immune dysregulation in HFpEF and stop disease progression.

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

“…Furthermore, the common biological processes among the three tissues were mainly related to cell cycle and immune response. These findings were consistent with those of previous studies, which demonstrated that cell cycle and immune response are closely related to diastolic dysfunction and impaired cardiac reserves ( Roh et al, 2020 ; Sava et al, 2020 ). Heart function is related to the flow dynamics of the cerebral artery, which may influence the gene expression in the cerebral artery and increase the incidence of cerebrovascular events ( Karahan et al, 2020 ).…”

“…For example, the biological processes of MLYCD , FKBP5 , PRKCD , and GDA were associated with energy metabolism and immune response, while those of SERPINE1 were associated with the inflammatory response. This was consistent with the pathological phenotypes, including immune dysregulation, metabolic dysfunction, and activation of chronic inflammation, of various tissues in patients with HFpEF ( Hage et al, 2020 ; Sava et al, 2020 ; Schiattarella et al, 2021 ).…”

Mesenchymal Stem/Stromal Cells in Immunity and Disease: A Better Understanding for an Improved Use

“…Sava, R.I. et al reviewed how MSCs efficiently target immune dysregulation in Heart failure with preserved ejection fraction (HFpEF) and stop disease progression. In vitro, MSCs may reduce the pro-inflammatory activity of immune cell types, and reduce myocardial fibrosis and improve diastolic function in vivo [14]. Zhou, Y. et al presented the recent advances regarding the immunomodulatory mechanisms of MSCs, and the importance of their paracrine factors in regenerative medicine and immune diseases [15].…”

Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19

“…As to the effects of MSCs on innate immunity, MSCs inhibit the responses of a group of major cells that involved in the innate immunity. MSCs have been shown to suppress DCs maturation (Spaggiari et al, 2009;Anderson et al, 2017), inhibit NK cells cytotoxic activity (Li et al, 2015), as well as stimulate conversion of macrophage into regulatory macrophages with anti-inflammatory properties (Uccelli and de Rosbo, 2015;Sava et al, 2020). Aside from exerting immunoregulatory effects, MSCs are capable of escaping the immune surveillance.…”