The Role of Hypoxia in Improving the Therapeutic Potential of Mesenchymal Stromal Cells. A Comparative Study From Healthy Lung and Congenital Pulmonary Airway Malformations in Infants

Abstract

Mesenchymal stromal cells (MSCs) play an important role in the field of regenerative medicine thanks to their immunomodulatory properties and their ability to secrete paracrine factors. The use of MSCs has also been tested in children with congenital lung diseases inducing fibrosis and a decrease in lung function. Congenital malformations of the pulmonary airways (CPAM) are the most frequently encountered lung lesion that results from defects in early development of airways. Despite the beneficial properties of MSCs, interventions aimed at improving the outcome of cell therapy are needed. Hypoxia may be an approach aimed to ameliorate the therapeutic potential of MSCs. In this regard, we evaluated the transcriptomic profile of MSCs collected from pediatric patients with CPAM, analyzing similarities and differences between healthy tissue (MSCs-lung) and cystic tissue (MSCs-CPAM) both in normoxia and in cells preconditioned with hypoxia (0.2%) for 24 h. Study results showed that hypoxia induces cell cycle activation, increasing in such a way the cell proliferation ability, and enhancing cell anaerobic metabolism in both MSCs-lung and MSCs-CPAM-lung. Additionally, hypoxia downregulated several pro-apoptotic genes preserving MSCs from apoptosis and, at the same time, improving their viability in both comparisons. Finally, data obtained indicates that hypoxia leads to a greater expression of genes involved in the regulation of the cytoskeleton in MSCs-lung than MSCs-CPAM.

Controlling fetal stress for preventing adverse health conditions in neonates and children

“…The role of dysbiosis in stressed mothers on fetal programming of HPA axis should be also considered ( 26 ). As reported in animal model, the stress-induced dysbiotic maternal vaginal microbiota contributes to the changes in hypothalamic gene expression of offspring following adulthood stress, leading to the HPA axis dysregulation ( 27 ).…”

Stem Cell Therapy and Rejuvenation, and Their Impact on Society

“…Leaving aside the risks of genetic rejuvenation, other less radical approaches have been experimentally developed to enhance stem cell renewal and potency while delaying senescence. Those include the stimulation of autophagy [ 23 , 24 ] and hypoxia [ 25 , 26 ], and the pharmacological regulation of different signaling pathways such as mTOR [ 15 , 23 ], PI3K/AKT [ 27 , 28 ], or Wnt/β-catenin [ 29 , 30 ]. Notably, these treatments induce changes at the epigenetic level, indirectly resulting in the higher expression of OSKM and other reprogramming factors by stem cells, but with fewer side effects than traditional reprogramming methods.…”