The present study demonstrated that MSCs exert a beneficial therapeutic effect on H9N2 AIV-induced lung injury in a murine model; treatment with MSCs results in improvements in both pulmonary inflammation and lung tissue organization. These findings have potentially important implications for the treatment of AI, which is an important clinical problem characterized by high patient morbidity and mortality.
Avian H9N2 viruses have been widespread in domestic poultry in Asian countries since the mid-1990s, with a mortality ranging from 5–30 % [29, 30]. Many studies have shown that H9N2 viruses can cause upper respiratory tract illnesses in humans. This indicates that the virus has evolved to cross the species barrier and is capable of infecting humans, bypassing intermediate hosts.
H9N2 viruses can activate the innate immune response. A hallmark of pulmonary infiltration associated with AI is the presence of infiltrating leukocytes [31, 32]. Leukocyte migration is directed largely by chemokines, and the inter-relationship of early-response cytokines, adhesion molecules, and chemokines orchestrates the recruitment of neutrophils into the lungs . In most studies, cytokines have been described as forming an inflammatory “cascade” or “network” in patients [30, 34]. Lung injury may be a direct consequence of this inflammatory response.
Adult stem cells or progenitor cells are being evaluated for the treatment of a number of diseases that currently have limited or no treatment options [35, 36]. Marrow-derived stem cells are hypothesized to be the source of lung regeneration and repair. An alternative source are exogenous stem/progenitor cells, delivered into the lung either intravenously via the trachea or by direct injection. Recently, many studies have confirmed that MSCs can engraft in the injured lung [37–39] and can even differentiate into lung epithelial cells in vivo. MSCs may also exhibit immunosuppressive properties, suggesting “immune-privilege”, and may even have certain immune regulation functions [40–42]. Therefore, MSCs may, in their own right, have beneficial effects in ALI.
Our data showed that H9N2 viral infection dramatically increases the expression of chemokines, including GM-CSF, MCP-1, KC, MIP-1α, and MIG, in both BALF and serum. However, MSC treatment decreases the expression of these chemokines. We also showed that MSC-treated mice have significantly reduced levels of some inflammatory cytokines (IL-1α, IL-6, TNF-α, and IFN-γ) and a corresponding increase in anti-inflammatory cytokines (IL-10). It is believed that IL-1α, IL-6, TNF-α, and IFN-γ play important roles in the development of ALI . These results are consistent with several previous studies. For example, in Mei’s study, treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice . Importantly, our in vivo experimental results suggest that the administration of MSCs can greatly improve the hypoxemia and histopathological changes of lung injury induced by H9N2 AIV infection. The data indicate that administration of MSCs results in a marked increase in survival rates, primarily due to a decrease in ALI. These results are not consistent with the findings of Lam et al. , who reported that MSC therapy fails to improve outcomes in experimental HIN1 influenza. We speculate that this might be a consequence of different pathogenic characteristics of different influenza viruses. It is known that avian influenza virus infection can lead to a “cytokine storm”. In consequence, the host cellular response may be different from that with H1N1 influenza virus infection.
We have, therefore, demonstrated that MSC-based cell therapy can attenuate the inflammatory reaction and injury in the lungs caused by H9N2 AIV exposure, as well as by reducing lung histopathological changes. These beneficial effects may be mediated by the downregulation of chemokines such as GM-CSF, MCP-1, KC, MIP-1α, and MIG, leading to the downregulation of inflammatory cytokines such as TNF-α, IL-1α, IL-6, and IFN-γ. Our findings provide further support for a prominent role of TLR4-dependent immune regulation in acute lung injury therapy. The quantity of stem cells used in our study was 1 × 105. This is much less than used by Wang et al. . We did not find an obvious stem cell niche in the lung tissue of mice. Therefore, we deduce that the immune regulation function of stem cells is via a paracrine mechanism.
On the other hand, it is possible that MSCs may be involved in the early stages of carcinogenesis through spontaneous transformation. In addition, it has been suggested that MSCs can modulate tumor growth and metastasis, although this remains controversial and poorly understood. Interestingly, different studies have reported contradicting findings, with some finding that MSCs promote tumor growth and others that they inhibit tumor growth. Therefore, the role of MSCs in avian influenza infection requires ongoing surveillance.