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Phenotypic characterization and differentiation potential of cells from human placenta: new approaches of stem cell theraphy for cystic fibrosis

Paracchini, Valentina (2011) Phenotypic characterization and differentiation potential of cells from human placenta: new approaches of stem cell theraphy for cystic fibrosis. [Doctoral Thesis]



Cystic fibrosis (CF) is the most frequent severe autosomal recessive disorder in the European population. The gene is located on the long arm of chromosome 7 and encodes for CFTR protein (Cystic Fibrosis Transmembrane Conductance Regulator). Despite the disease involves different organs, the most clinically relevant symptoms are found in the lung. Recently, given the monogenic nature of CF, different gene therapy strategies have been developed, but the results show that the correction of the defect is only temporary. Therefore, a novel approach based on stem cell-based therapy for reconstitution of the airway epithelium and CFTR expression should be explored. CF is a potential model disease for stem cell therapy because of the persistent lung inflammation that leads to damage and remodeling, and can promote engraftment of stem cells. If stem cells, transferred through autologous or heterologous transplant, would harbour in stem niches of respiratory epithelium, then the restoration of genetic and cellular damage will be definitive. In the last years, several cell populations derived from adult bone marrow, amniotic fluid or umbilical cord blood, have been shown to differentiate in different epithelia, including respiratory. Even if the in vivo efficiency of bone marrow stem cells to differentiate in airway epithelium is very low, recent studies demonstrate that a small percentage of corrected cells is needed to revert the defect. Bone marrow mesenchymal stem cells are not without drawbacks, e.g. they are limited in numbers and lack well-defined markers required for their purification. One approach to overcome these limitations is to consider alternative sources of stem cells capable of repopulating damaged respiratory epithelium. In the present study, we evaluated the possibility of obtaining stem cells from an ethically acceptable source as human placenta. As a potential source of cells for application in CF therapy, the placenta has the advantage of being a natural by-product of birth which is often simply discarded, while harvest of term amniotic membrane does not pose any risk to the mother or newborn. We demonstrated that amniotic membrane is a fetal tissue rich in cells with stem cell characteristics and with the capacity to remain “plastic” in their differentiation options. Furthermore, amniotic cells display features as low immunogenicity and non tumorigenicity. For the first time, our results provided evidence that human amniotic epithelial cells (hAECs) and amniotic mesenchimal stromal cells (hAMSCs) can be induced in vitro to express markers of airway epithelial phenotype, like CFTR and ZO-1, particularly when co-cultivated with CF human epithelial bronchial cells, and so have the potential to differentiate into airway epithelial cells. Overall, our data showed that these cells may contribute to partial correction of the CF phenotype and are very likely an ideal candidate for cell-based therapy for CF. Whether the beneficial effects of placenta-derived cells are due to differentiation of the transplanted cells themselves or to paracrine actions on the surrounding host tissue in order to reduce inflammation and promote regeneration remains to be fully elucidated. In any case, the promising data obtained to date constitute compelling evidence regarding the potential utility of these cells for clinical application. Future studies testing these cells in in vivo model, will help in finding a strategy of cell therapy for the cure of respiratory disease of CF, directly transferable to CF patients.

Item Type:Doctoral Thesis
Date:18 January 2011
Tutor:Colombo, Carla
PhD classes:Ciclo 23 > Terapia pediatrica e farmacologia dello sviluppo
Coordinator:Galanello, Renzo
Institution:Universita' degli Studi di Cagliari
Divisions:Dipartimenti (fino a dicembre 2011) > Dipartimento di Scienze biomediche e biotecnologie
Subjects:Area 06 - Scienze mediche > MED/05 Patologia clinica
Uncontrolled Keywords:cellule staminali, placenta, fibrosi cistica, stem cells, cystic fibrosis
ID Code:587
Deposited On:24 Mar 2011 16:04

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