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Editorials and Perspectives: Analysis and Commentary

Lung Transplantation: The Yin and Yang of Mesenchymal Stem Cells

Kirby, John A.; O'Boyle, Graeme

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doi: 10.1097/TP.0b013e318222ca4c
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The lung is particularly vulnerable to function-limiting, structural damage after allogeneic transplantation. This is mediated by multiple mechanisms, including early innate and adaptive immune responses that are followed all too frequently by fibrotic remodeling. Within 5 years, this produces the largely untreatable bronchiolitis obliterans syndrome in the majority of lung transplant patients, leading to significant morbidity and mortality. Recent studies have focused on the contribution of lung-resident mesenchymal stem cells (MSCs) to both positive and negative regulation of these graft-damaging processes.

Rare MSCs were first identified in the bone marrow; but these heterogeneous, self-renewing multipotent cells have now been found in most tissues, including those of the lung. Although MSCs lack unique markers, it is known that they can express a range of functional receptors that stimulate migration toward chemokines. This includes a response to CXCL8, which has been identified at increased levels in bronchoalveolar lavage (BAL) fluid after lung transplantation (1).

It is reasonable to expect stem cells to repair damaged tissues most efficiently within an antiinflammatory environment that spares these critical cells and their differentiated progeny from damage. A range of studies has now shown that MSC can regulate inflammatory processes directly by influencing a range of immune cell functions. For example, MSC can inhibit the maturation of blood monocytes into dendritic cells and the acquisition of an antigen-presenting, dendritic cell phenotype by reducing the expression of class II major histocompatibility complex antigens, costimulatory molecules, and interleukin-12. These stem cells can also limit the cytotoxic function of natural killer cells and the tissue- damaging respiratory burst, which normally follows neutrophil activation. It has been suggested that the expression by MSC of decoy receptors such as the Duffy antigen receptor of chemokines might remove proinflammatory chemokines, preventing leukocyte recruitment.

Further studies have shown that lung-derived MSC can limit the adaptive immune function of T lymphocytes (2). This may be of particular relevance for the prevention of antigen-specific damage during acute lung allograft rejection. Evidence suggests that the inhibition of T-cell functions by MSC is not major histocompatibility complex restricted, allowing both tissue resident (donor) and infiltrating (recipient) MSC to modulate the immune response in the setting of a lung allograft. The mechanisms by which MSC inhibit T-cell activity remain unclear, although apoptotic deletion is not induced. A number of candidates have been reported, including inhibition of interferon-γ secretion, production of immunosuppressive matrix metalloproteinase-2 and -9, inhibition of T-cell cytotoxicity, and increasing the proliferation and function of regulatory T cells. Further research has shown that MSC also inhibit B-cell proliferation and differentiation, although antibody production may be spared. In many cases, MSC-lymphocyte contact is not required, suggesting the involvement of soluble factors; it may be relevant that MSC are known to produce immunoregulatory transforming growth factor (TGF)-β1 constitutively (3).

Although the immunosuppressive properties of MSC may be beneficial for lung allograft survival, these cells also have functions that might damage lung tissues. Indeed, their secretion of TGF-β1 alone might simultaneously mediate both effects. It is well known that TGF-β1 can produce function-damaging pulmonary fibrosis by expanding the number of activated fibroblasts, leading to excessive deposition of organized extracellular matrix. The source of these fibroblasts is currently controversial, but they are most likely generated directly by airway epithelial to mesenchymal cell transition or by the proliferation of lung-resident or bone marrow– derived precursor cells. The number of MSC within the cell population recovered from transplanted lungs by BAL is prognostic of the development of bronchiolitis obliterans syndrome. Previous studies have also associated obliterative bronchiolitis with the presence of increased levels of endothelin (ET)-1 in BAL fluid from transplanted lungs (4).

ET-1 is a 21-amino acid peptide principally produced by endothelial cells to regulate blood pressure through stimulation of G-protein coupled receptors on vascular endothelial and smooth muscle cells. However, it is now clear that ET-1 can also stimulate the accumulation of fibroblasts during pulmonary fibrosis. This issue of Transplantation contains an important article by Salama et al. (5), which offers a potential route to integration of the pathogenetic roles played by dysregulated MSC and ET-1 in transplanted lungs. Specifically, it is reported that the rate of MSC proliferation is increased by ET-1 during the development of obliterative bronchiolitis, with the responsive cells migrating toward ET-1 and differentiating into an α-smooth muscle actin- expressing, myofibroblastic phenotype. In a further twist, the authors show that ET-1–responsive MSCs are stimulated to release further ET-1, thereby providing a route to reinforcement of lung allograft pathology by positive feedback. Previous authors have suggested that the profibrotic functions of ET-1 in the lung are mediated at least in part by cooperation with the TGF-β signaling pathway (6); this convergence might also provide a link between ET-1 and the immunoregulatory activities of MSC.


1. Fisher AJ, Donnelly SC, Hirani N, et al. Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation. Am J Respir Crit Care Med 2001; 163: 259.
2. Jarvinen L, Badri L, Wettlaufer S, et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181: 4389.
3. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838.
4. Salama M, Jaksch P, Andrukhova O, et al. Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients. J Thorac Cardiovasc Surg 2010; 140: 1422.
5. Salama M, Andrukhova O, Jaksch P, et al. Endothelin-1 governs proliferation and migration of bronchoalveolar lavage-derived lung mesenchymal stem cells in bronchiolitis obliterans syndrome. Transplantation 2011; 92: 155.
6. Ross B, D'Orleans-Juste P, Giaid A. Potential role of endothelin-1 in pulmonary fibrosis: From the bench to the clinic. Am J Respir Cell Mol Biol 2010; 42: 16.
© 2011 Lippincott Williams & Wilkins, Inc.