At present, allogeneic lung transplantation is the only

At present, allogeneic lung transplantation is the only approach to treat patients withterminal pulmonary failure. However, continuing donor organ shortage results in a30% preoperative lethality of potential lung transplant (LTx) recipients on waiting lists.Despite significant progress in surgical technique (e.g.

minimal invasive technique)and therapy of acute rejection as well as management of pulmonary infections,postoperative survival times after LTx are still significantly less when compared tothose after transplantation of other parenchymal organs (Trulock et al., 2007).Obviously, alternative therapeutic approaches are urgently needed. At this point, thequestion arises, how can stem cell-based approaches be used in treating severe lungdisorders? Stem cell-based therapies of genetic disorders are simpler to establish whencompared to treatment of other respiratory diseases. Indeed, numerous studies havefocused on the application of gene therapy in the correction of hereditary lung disorders, including attempts to treat alpha-1-antitrypsin deficiency (Rosenfeld et al.

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,1991), cystic fibrosis (Rosenecker et al., 2006; Sueblinvong et al., 2007; Wang et al.

,2005) or surfactant protein deficiency (Yei et al., 1994). Several obstracles should beovercome before approaches aimed at correcting gene deficiencies using geneticallymodified stem cell derivatives can be utilized. These include general technologicalaspects of therapeutic gene transfer, the stem cell source, expansion, specificdifferentiation and potential purification of stem cell progeny as well as the mode ofdelivery. There is no evidence that a single lung stem cell, as in the hematopoietic system,gives rise to all cell lineages during homeostasis or repair. However, differentiatedepithelia are derived from local epithelial progenitors.

Although mesenchymalprogenitors,in the embryonic mouse lung, have regional specificity (Kumar et al.,2014), it is unclear whether mesenchymal progenitors in the adult lungs are similarlygeographically localized. The adult lung is a highly quiescent tissue with a remarkablylow level of cellular turnover (Peng et al., 2015). Although it is not yet clear whetherthis pathway functions similarly in the human lung, this important observation may berelevant to the pathogenesis of lung diseases characterized by aberrant repair andregeneration. Although in-vitro gene transfer into stem cells is easier to achieve than efficient invivo gene transfer into pulmonary target cells, this does not guarantee stable long-term expression at an optimal level. If integrating vectors (e.

g. gamma retroviral orlentiviral ones) are applied, the risk of malignant transformation should be consideredand ideally, appropriate cell clones should be selected (Li et al., 2002). Importantly, asuitable stem cell source should be identified that can be isolated or generated,cultured and expanded. Whether the optimal stem cell type is an exogenous adultstem cell (e.g. from bone marrow) or an endogenous lung stem cell, which is moredifficult to isolate especially in case of autologous cells, or a pluripotent stem cell e.

g.an induced pluripotent stem cell (Takahashi et al., 2007; Yu et al.

, 2007) that can beeasily collected mainly depends on the target disease. For example, for treatment ofpatients with cystic fibrosis or surfactant protein B (SP-B) deficiency, stem cellderived bronchial (Coraux et al., 2005) or alveolar epithelial cells should begenerated. Efforts are already underway to differentiate functional type II alveolar epithelial (AT2)cells (Rippon et al.

, 2006; Wang et al., 2007; Winkler et al., 2008); the exclusivenatural producers of SP-C, for future therapy of surfactant protein C (SP-C)deficiency. For treatment of alpha-1-antitrypsin deficiency, several cell types such ashepatocytes, the principle natural source of alpha-1-anti- trypsin, AT2 cells andalveolar macrophages are likely candidates (Boutten et al., 1998). Although in earlystage cases, alpha-1-antitrypsin deficiency may be treatable by transplantation oftransgenic stem cell derivatives; this possibility appears less likely in advancedstages following massive development of emphysema (Fregonese, Stolk, 2008). Circulating blood cells including those derived from bone marrow contribute to therepair of LPS- (Yamada et al.

, 2004), irradiation- (Abe et al., 2004; Theise et al.,2002) elastase- (Ishizawa et al., 2004; Murakami et al., 2005), naphthalene- (Wonget al., 2007) or bleomycin- mediated acute lung injuries, thus preventing pathologicalconsequences including emphysema or fibrosis. However, evidence for reversal of manifested pulmonary fibrosis or emphysema is very scarce (Ortiz et al.

, 2003;Rojaset al., 2005). 2. Human Lung Stem Cells Human lung stem cells can generate bronchioles, approximately 30 to 250 ?m indiameter, as well as small and intermediate-sized pulmonary arterioles 20 to 70 ?m indiameter (Kajstura et al., 2011).

The average cell volume of type I alveolar epithelialcells is 700 to 900 ?m in mouse and 1800 ?m in humans (Kelsey et al., 2009;Wisnivesky et al., 2005), while the smooth endoplasmic reticulum occupies morethan 40% of the cytoplasm in murine Clara cells, as compared with less than 10% inhuman Clara cells (Howlader et al., 2011). These determinants are important, sincethe formation of chimeric lung generated by the mouse milieu may not bereproducible in injured human lung tissue. c-Kit has been used as a stem-cell marker to identify and localize human lung stemcells (Kajstura et al.

, 2011) have described the evidence for. c-Kit–positive cells inadult lungs are multi-potential (Oshizawa et al., 2013).

Such cells are scattered inlung mesenchyme and co-expressed endothelial marker CD34. Three-dimensionalreconstruction views of double immune-staining revealed vascular-tube formation byc-Kit–positive and CD34-positive cells. The co-expression of c-Kit and CD34 wasconsistently observed between 13 and 40 gestational weeks.

In contrast, lung buds’epithelial cells do not express c-Kit, indicating that c-Kit–positive cells contain alreadyinitiated heterogeneous progenitor populations thus describing c-Kit–positive cells asmulti-potential human lung stem cells may be incorrect (Fujino et al., 2011).