Paracrine Effects and Heterogeneity of Marrow-Derived Stem/Progenitor Cells: Relevance for the Treatment of Respiratory Diseases

Abstract

Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders.

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…Consistently we detected only a few, preferably single donor cells in WTI lung sections while circulating enhanced green fluorescent protein [EGFP(+)] MSCs could be detected in peripheral blood even 25 weeks after transplantation, supporting the idea that tissue protection is due to paracrine signaling (44). Today it is widely accepted that the positive outcome of MSC therapy is not due to a direct engraftment of these cells into the lung, for example, as endothelial and epithelial cells, instead paracrine factors are now considered to be the main mechanism through which stem and progenitor cells exert their therapeutic effect (13). Herein, it was suggested that MSCs may mediate their function through a ''hit and run'' mechanism, where MSCs, once temporarily localized to the lung, may provide a local source of trophic factors in the pulmonary environment (8,13).…”

“…Today it is widely accepted that the positive outcome of MSC therapy is not due to a direct engraftment of these cells into the lung, for example, as endothelial and epithelial cells, instead paracrine factors are now considered to be the main mechanism through which stem and progenitor cells exert their therapeutic effect (13). Herein, it was suggested that MSCs may mediate their function through a ''hit and run'' mechanism, where MSCs, once temporarily localized to the lung, may provide a local source of trophic factors in the pulmonary environment (8,13).…”

“…We are well aware of the fact that tissue-resident MSCs are heterogeneous and that different MSC subsets exist. The characterization and/or isolation of the stem cell subpopulations represent a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders (13). Primary lung MSCs that were enriched in the CD90/CD105 mononuclear cell fraction were shown to be located perivascularly (67).…”

Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis

“…MSCs were first identified in the bone marrow in 1976 (24) and have since been shown to express a broad spectrum of secreted molecules, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, IL-10, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1, HGF, KGF, prostaglandin PGE2, amongst others (17,18). Through the action of these soluble mediators, BM-MSCs have been shown to modulate the activation, proliferation, and downstream effects of inflammatory and immune cells in both the innate and adaptive immune systems; including neutrophils, macrophages and lymphocytes (25,26).…”

“…However, numerous studies have shown that lung epithelial or endothelial cells are rarely derived from BM-MSCs (15,16), therefore engraftment in the lung as structural epithelium or endothelium is not currently considered the mechanism by which BM-MSCs can repair lung tissue (17). Previous evidence has shown however, that BM-MSCs can migrate to injured tissues, communicate with injured parenchyma cells, and function in the wound healing process through the production of paracrine-soluble cytokines and growth factors, which modulate the regeneration of the epithelium and endothelium (18). Previous research has revealed that systemic infusion of conditioned medium (CM) obtained from mesenchymal stem cells (MSCs) leads to a hepato-protective response in the acutely injured liver, specifically by inhibition of cell apoptosis and stimulation of reparative programs (19).…”