Cystic Fibrosis (CF) is the most common autosomal recessive genetic disorder in Caucasian population. It is caused by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions mainly as anion channel and is primarily expressed in the apical membrane of secretory epithelia. Lung disease, characterized by airway obstruction, inflammation and bacterial infection is the leading cause of death. At variance with some pharmacological approaches, no efficacious gene and cell therapy have been proved to date. Advances in the application of stem cells have generated hope that, by the use of this new potential tool, it will be possible to provide therapeutic treatments for CF, where current therapies are still inadequate. Our laboratory worked for several years on mesoangioblasts (MABs), blood vessel-associated progenitor cells that can differentiate into different mesoderm cell types. When delivered in the arterial circulation, MABs cross the vessel wall and participate to skeletal muscle regeneration, ameliorating signs of Muscular Dystrophies in different pre-clinical animal models. For these reasons they have been used in a trial in human patients that definitely demonstrated that the transplantation of donor MABs in humans is feasible and safe. During studies on MABs isolated from adult mouse skeletal muscle (mMABs) we observed that, when systemically transplanted in healthy, wild type mouse model, mMABs surprisingly engraft lung, tracheal and intestinal epithelium up to one month from a single transplantation trough the caudal vein. Due to this striking evidence, included MAB capability to express CFTR, we proposed to investigate on a possible use of MABs as a therapeutic tool for CF disease. In this work we present strong evidence that the transplantation of mMABs in two different CF mouse models leads to a rescue of CF phenotype. We demonstrated that mMABs engraft the respiratory and the intestinal epithelium in CF mice up to six months from their single transplantation, leading to a functional rescue of CFTR-dependent chloride current. Notably, once engrafted in the epithelium, mMABs express typical epithelial markers, revealing an unexpected and powerful relevant ability of MABs to differentiate into epithelial cells, thus contributing to airways and intestine homeostasis and biology. Overall, these data demonstrate that MABs are eligible for a cell-based therapy of CF.

VESSEL ASSOCIATED PROGENITOR CELLS AS A PROMISING CELL-BASED APPROACH TO TREAT CYSTIC FIBROSIS DISEASE / C. Vezzali ; tutor: G. Messina. - : . Università degli Studi di Milano, 2016 May 25. ((28. ciclo, Anno Accademico 2015. [10.13130/vezzali-chiara_phd2016-05-25].

VESSEL ASSOCIATED PROGENITOR CELLS AS A PROMISING CELL-BASED APPROACH TO TREAT CYSTIC FIBROSIS DISEASE

C. Vezzali
2016-05-25

Abstract

Cystic Fibrosis (CF) is the most common autosomal recessive genetic disorder in Caucasian population. It is caused by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions mainly as anion channel and is primarily expressed in the apical membrane of secretory epithelia. Lung disease, characterized by airway obstruction, inflammation and bacterial infection is the leading cause of death. At variance with some pharmacological approaches, no efficacious gene and cell therapy have been proved to date. Advances in the application of stem cells have generated hope that, by the use of this new potential tool, it will be possible to provide therapeutic treatments for CF, where current therapies are still inadequate. Our laboratory worked for several years on mesoangioblasts (MABs), blood vessel-associated progenitor cells that can differentiate into different mesoderm cell types. When delivered in the arterial circulation, MABs cross the vessel wall and participate to skeletal muscle regeneration, ameliorating signs of Muscular Dystrophies in different pre-clinical animal models. For these reasons they have been used in a trial in human patients that definitely demonstrated that the transplantation of donor MABs in humans is feasible and safe. During studies on MABs isolated from adult mouse skeletal muscle (mMABs) we observed that, when systemically transplanted in healthy, wild type mouse model, mMABs surprisingly engraft lung, tracheal and intestinal epithelium up to one month from a single transplantation trough the caudal vein. Due to this striking evidence, included MAB capability to express CFTR, we proposed to investigate on a possible use of MABs as a therapeutic tool for CF disease. In this work we present strong evidence that the transplantation of mMABs in two different CF mouse models leads to a rescue of CF phenotype. We demonstrated that mMABs engraft the respiratory and the intestinal epithelium in CF mice up to six months from their single transplantation, leading to a functional rescue of CFTR-dependent chloride current. Notably, once engrafted in the epithelium, mMABs express typical epithelial markers, revealing an unexpected and powerful relevant ability of MABs to differentiate into epithelial cells, thus contributing to airways and intestine homeostasis and biology. Overall, these data demonstrate that MABs are eligible for a cell-based therapy of CF.
MESSINA, GRAZIELLA
Cystic Fibrosis; Mesoangioblasts; Cell Therapy
Settore BIO/10 - Biochimica
Settore BIO/11 - Biologia Molecolare
VESSEL ASSOCIATED PROGENITOR CELLS AS A PROMISING CELL-BASED APPROACH TO TREAT CYSTIC FIBROSIS DISEASE / C. Vezzali ; tutor: G. Messina. - : . Università degli Studi di Milano, 2016 May 25. ((28. ciclo, Anno Accademico 2015. [10.13130/vezzali-chiara_phd2016-05-25].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/414097
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