Original pre-clinical science
Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation

https://doi.org/10.1016/j.healun.2010.09.012Get rights and content

Background

Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB). Presently, complete understanding of the mechanisms of OB has been elusive. Bone marrow–derived mesenchymal stem cells (MSC) have been shown to modulate repair of the injured lung in multiple disease models. We hypothesized that the injection of MSC would prevent development of early airway obstruction (AO) in the heterotopic tracheal transplant model.

Methods

Forty-four tracheas from BALB/c and C57BL/6 donors were transplanted into 22 C57BL/6 recipients. At the time of transplant, 13 of the allogeneic recipient mice were injected with 5 × 105 MSC from various murine sources. To confirm the role of the immune response in the generation of AO we used a permeable inhibitor of nuclear factor-kappaB (NF-κB) in 11 recipients after transplantation with 22 BALB/c tracheas.

Results

After transplantation, administration of MSC inhibited intraluminal obstruction by collagen in 98% of the mice and transforming factor-beta (TGF-β) expression decreased to levels similar to those observed in isograft controls. These effects were associated with a significant (p < 0.05) increase in expression of the anti-inflammatory cytokine interleukin-10 (IL-10). NF-κB inhibitor showed decreased expression of transforming growth factor-beta (TGF-β) in the Day 7 and Day 14 groups, resulting in a 60% reduction of luminal obstruction as well as a decrease in inflammatory cells to the airway.

Conclusion

Our observations suggest that administration of MSC prevents development of airway occlusion in a mouse model, probably through the modulated immune response altering TGF-β expression.

Section snippets

Animal maintenance

Experiments were conducted using 10- to 14-week-old female C57BL/6, BALB/c and CH3 mice (Jackson Laboratories, Bar Harbor, ME). The animals were housed in cages and maintained on a 12/12-hour light/dark cycle at the Division of Animal Resources, Emory University. All animals had free access to food and water. All animal protocols were reviewed and approved by the institutional animal care and use committee.

Trachea grafting

Tracheas were transplanted as previously described.6, 13, 14 Briefly, the mice were

MSC attenuate airway obstruction in allograft transplant recipients

Donor tracheal segments from BALB/c and C57BL/6 were heterotopically transplanted into C57BL/6 recipients. Group assignment was defined by the donating species. Allograft controls were made up of BALB/c tracheas transplanted into C57BL/6 recipients. Isograft controls were made up of C57BL/6 tracheas transplanted into C57BL/6 recipients. Tracheas were harvested on Day 10 and homogenized for Western blot analysis or fixed in formalin and then paraffin and sectioned for staining with H&E, Masson's

Discussion

In this study we investigated a potential therapeutic intervention to prevent the development of airway obstruction in a murine heterotopic model of lung transplantation and to further characterize its mechanisms. Based on previous studies, we hypothesized that MSC would modulate the pro-fibrotic response of allogeneic transplant. We presumed this would be mediated through modulatory effects on TGF-β.

To demonstrate the impact of MSC on the development of AO we used the heterotopic tracheal

Disclosure statement

This research was supported by the National Heart Lung and Blood Institute (5K01HL084683-02), the American Federation for Aging Research, Emory University (URC 2003100) and the McKelvey Center for Lung Transplantation at Emory University. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S.

References (19)

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Cited by (34)

  • Bone Marrow-derived Mesenchymal Stem Cells and Chronic Allograft Disease in a Bronchiolitis Obliterans Animal Model

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    Another example of this is the finding of BMSC (CrY+) taking part of the walls of neovessels, which are morphologically identical to endothelial cells (Fig. 5). Previous heterotopic tracheal transplant models have shown the capacity of stem cells to attenuate histopathological changes of BO after either topical or systemic administration.34–36 In this study, we have found that BMSC are able to nest and survive, detect an injury scenario, modify the histopathological course of BO lesions, and repair the structure.

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    Our group also observed in a small pilot study that MSCs improved steroid-resistant chronic GVHD (cGVHD) with lung manifestations [15]. Preclinical studies have provided rationales for use of MSCs in BOS [16-18]. Accordingly, in this prospective cohort study, we assessed the efficacy and safety of MSCs combined with azithromycin and prednisone on lung function of patients with HSCT-related BOS.

  • Cardiopulmonary and histological characterization of an acute rat lung injury model demonstrating safety of mesenchymal stromal cell infusion

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    These results underscore the importance of evaluating the safety of MSC injections in animal models of lung injury before the initiation of human clinical studies, especially for pulmonary disorders. It has been shown that MSCs can protect the lungs from acute lung injury induced by bleomycin and reduce lung transplant rejection in rodent models [11–16]. However, detailed and clinically relevant pulmonary function tests (PFTs) have not been assessed in detail in any animal model [17].

  • Hepatocyte growth factor enhances the inflammation-alleviating effect of umbilical cord-derived mesenchymal stromal cells in a bronchiolitis obliterans model

    2016, Cytotherapy
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    Also, IL-10 may play a potential role in the development of experimental BO. In a murine model of allotropic tracheal transplantation, MSCs could induce an increase in IL-10 levels [20]. Our study showed that MSC treatment could increase the expression level of IL-10 that was down-regulated by heterograft not only in the transplanted trachea but also in the peripheral blood.

  • Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway

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    For example, MSC express B7 homolog 1 (B7-H1), which interacts with CD28, blocking an essential T-cell co-stimulatory pathway for the initiation of antigen-specific humoral and cell-mediated immune responses (13). We determined that in vivo delivery of intra-tracheal BMC had variable effects on allograft rejection, although the reduction in rejection was broadly similar to a recently reported study (26). Although not common, others have reported that MSC are not always immunosuppressive (27,28).

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