Stem cells are undifferentiated cell groups that have varying degrees of self-renewal and differentiation capacity.
According to their origin, they can be divided into embryonic stem cells and adult stem cells. Despite having the ability to generate any terminally differentiated cell in the body, embryonic stem cells present important issues that limit their use; thus, most studies have focused on therapy with adult stem cells.
Several experimental studies have demonstrated that both recruited endogenous and delivered exogenous stem cells can home to and/or participate in rebuilding of missing or damaged lung tissue. Thus, there is a great deal of interest and research into stem cell therapies for lung diseases with no current effective treatment.
This article presents a critical review of advances in the field of stem cell biology, as well as highlighting the effects of mesenchymal stem cell (MSC) therapy in acute lung injury (ALI) /acute respiratory distress syndrome (ARDS), pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
Adult stem cells
Adult stem cells (ASC) are the term used to describe postnatal stem cells that remain in body tissues throughout life. These cells can be found in well-protected, innervated, and vascularized niches, from which they are recruited to maintain tissue homeostasis.
If required, stem cells may undergo asymmetric cell division, generating one stem cell and a committed progenitor.
A number of specialized ASC niches have recently been identified in lung tissue in addition to Clara cells and type II pneumocytes (precursors of airway and alveolar epithelial cells, respectively): intercartilaginous regions of the tracheobronchial tree and neuroepithelial bodies in the bronchioles and bronchoalveolar duct junctions, which may significantly contribute to natural turnover or rebuilding of injured lung tissue. The angiogenic factor and fibroblast growth factor-2 (FGF-2) seems to be essential for resident stem cell activation in the lung.
ASC from various organs may be recruited for lung repair. Bone marrow is the main source of adult hematopoietic stem cells and mesenchymal stem cells.
Bone marrow cells
The term bone marrow-derived mononuclear cells (BMDMC) includes both hematopoietic and mesenchymal (nonhematopoietic) stem cell types. Hematopoietic stem cells (HSC) are nonadherent cells that have the ability to proliferate and differentiate into blood cells.
These are rare cells that represent only 1 in 104 to 1 in 105 of total blood cells in bone marrow, identified by CD34 and CD45 surface markers. During postnatal life, a steady state is established, in which the HSC pool size is maintained by regulation of self-renewal and differentiation.
This is possible because the bone marrow contains specialized niches in which the multipotency of HSC is preserved through cell division, while their progeny are directed towards lineage differentiation.
To define MSC (mesenchymal stem cells), minimum consensus criteria should be adopted:
(1) Selection for a plastic-adherent cell population in standard culture conditions;
(2) Expression of CD105, CD73, and CD90 and no expression of CD45, CD34, CD14, CD11b, CD79-, CD19, or HLA-DR surface molecules; and
(3) Ability to differentiate into adipocytes, osteocytes, and chondrocytes in vitro
MSC are found in the stromal fraction of bone marrow, and provide support to hematopoiesis. Mesenchymal stemlike cells have also been recently identified in different tissues: adult peripheral blood, adipose tissue, skin, and lung.
MSC are capable of adopting the morphology and phenotype of parenchymal cells of many nonhematopoietic tissues, including the lung, where they can increase the number of fibroblast-like cells and differentiate into bronchial epithelial cells and alveolar type I and II pneumocytes.
Mechanism of action
MSC may promote lung tissue repair through plasticity (the ability of ASC to cross lineage barriers and to adopt the expression profiles and functional phenotypes of cells unique to other tissues). The acquisition of a new phenotype by MSC may occur in different ways:
- Differentiation: process by which an undifferentiated cell becomes structurally and functionally more complex and specialized. In the lung, MSC differentiation into more specialized type II pneumocytes may contribute to repair of disrupted alveolar surfaces, characteristic of many respiratory diseases.
- Transdifferentiation: refers to the ability of a committed cell to change its gene expression pattern without cell fusion. So far, no data have been published to support this theory.
- Cell fusion: MSC fusion with other cell types to form a heterokaryon, converting its gene expression pattern to that of the fusion partner. A recent experimental study has demonstrated that 20–50% of lung epithelial cells derived from MSC result from cell fusion.
- Lateral transfer of RNA: uptake of messenger RNA (mRNA) microvesicles derived from other cell types, with expression of protein translated from the mRNA that was taken up.
Since several studies have demonstrated that the effects of these cells on organ systems are currently attributed to a paracrine effect—an ability to secrete soluble factors that modulate immune responses of different diseases. This mechanism was first identified by observing that systemic administration of MSC was able to inhibit expression of several proinflammatory and profibrogenic cytokines in models of ALI and pulmonary fibrosis. In short, MSC or BMDMC did not act only through plasticity, but also through paracrine effects, interfering significantly with the pathophysiological processes of lung diseases.
Stem cell therapy
Stem cell therapy appears to be a promising strategy for treatment of many respiratory diseases with no effective treatment, such as ALI and its severe form ARDS, pulmonary fibrosis, and COPD. These lung disorders differ substantially in their time course and pathophysiology, but have one feature in common, namely the ability of the alveolar epithelium to recover after injury.
Stem cells in pulmonary fibrosis
Pulmonary fibrosis is a devastating disease with high mortality rate and no effective therapy to reverse or delay the natural course of disease. After disappointment with the effects of anti-inflammatory treatment, evidence has shown a role of abnormal alveolar repair and remodeling in the pathophysiology of fibrosis. Therefore, since MSC can yield alveolar epithelial repair and inhibit fibrogenesis, MSC therapy is a possible therapeutic tool for pulmonary fibrosis.
Stem cells in chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease is characterized by repeated repair and destruction processes, with subsequent tissue remodeling as well as sustained and irreversible airflow limitation. No effective therapy is available for COPD.
A reduced number of progenitor cells has been observed in end-stage COPD patients and in experimental emphysema induced by elastase . These progenitor cells differentiate into many types of lung cells, mainly mature endothelial cells. Other studies have demonstrated that nonsmoker COPD patients present an increase in the number of progenitor cells that is proportional to bronchial obstruction and arterial oxygen tension, suggesting an intriguing compensatory effect of hypoxia on progenitor cell mobilization.
Different routes of administration have been described: intravenous, intra-arterial, and intratracheal.
A recent study has demonstrated that intravenous administration of MSC results in higher pulmonary engraftment compared with BMDMC and multipotent adult progenitor cells (MAPC). This occurs because MSC are larger and express many adhesion molecules, such as VCAM-1 and P-selectin, which facilitates their retention in the lung.
Once delivered, MSC are recruited to the injured tissue, where they promote release of cytokines and growth factors, contributing to a positive therapeutic outcome. In this line, the future of MSC therapy may lie in stimulation of specific mediators, such as growth factors and anti-inflammatory cytokines that participate in cell recruitment as well as endothelium and epithelium repair.
Some ongoing clinical trials are testing the safety and feasibility of cell-based therapy in respiratory diseases.
Conclusion: There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair.