Implications physiopathologiques de la Nestine lors du remodelage pulmonaire et cardiaque à la suite de l’infarctus du myocarde, du diabète et de l’hypertension pulmonaire

It is well established that the intermediate filamentous protein Nestin is expressed during wound healing and fibrotic remodeling. Furthermore, we have identified Nestin expression in two distinct populations directly implicated in reparative and reactive fibrosis. The adult rodent heart contains a resident population of neural progenitor/stem cells that express Nestin and identified as a cellular substrate of cardiac angiogenesis and neurogenesis. Moreover, Nestin is also expressed in cardiac scar myofibroblasts and the intermediate filament protein plays a direct role in proliferation. Thus, the general aim of the present thesis was to better understand the cellular events implicated in the neurogenic response of neural progenitor/stem cells during cardiac reparative fibrosis and to explore whether the appearance of Nestin(+)-fibroblasts was associated with reactive fibrotic response secondary to pulmonary remodeling. The first study revealed that the transient upregulation of growth associated protein 43 (GAP43) represents a transition event during the acquisition of a neuronal-like phenotype by cardiac resident neural progenitor/stem cells in the scar of the infarcted rat heart. Furthermore, the superimposition of a type 1 diabetic environment, via the single injection of streptozotocin in rats, abrogated the neurogenic response of cardiac resident neural progenitor/stem cells to ischemia and 6-hydroxydopamine, respectively. The second study has demonstrated that the development of acute pulmonary fibrosis secondary to myocardial infarction of the adult rat heart was associated with the increased expression of Nestin protein levels and appearance of Nestin(+)-myofibroblasts. Furthermore, the treatment of pulmonary fibroblasts with putative pro-fibrotic peptide growth factors increased Nestin protein levels. Lastly, in the lungs of type 1 diabetic rats, the absence of a reactive fibrotic response was associated with a significant downregulation of Nestin protein/mRNA levels. Finally, the third study represented an extension of the second study and examined chronic lung remodeling in an established model of pulmonary hypertension. The lungs of adult male rats subjected to 3 weeks of hypobaric hypoxia were associated with vascular remodeling, reactive fibrosis and increased Nestin protein and mRNA levels. Moreover, Nestin, rather than smooth muscle α-actin expression was identified as a more relevant marker of activated pulmonary fibroblasts. Furthermore, the appearance of activated pulmonary fibroblasts may be derived in part from resident fibroblasts and secondary to endothelial-mesenchymal transition and epithelial-mesenchymal transition. Collectively, these studies have demonstrated that distinct populations of Nestin-expressing cells play a seminal role in cardiac reparative fibrosis and pulmonary reactive fibrosis.

Keyphrases: Nestin, Myocardial infarction, Neural progenitor/stem cell, Neurogenesis, Diabetes, Pulmonary hypertension, Reparative and reactive fibrosis, Fibroblasts, Endothelial-mesenchymal transition, Epithelial-mesenchymal transition