Mesenchymal Stromal Cells Reduced Lung Cell Aging in Mice
Mesenchymal stromal cells (MSCs) lessened lung scarring by reducing idiopathic pulmonary fibrosis (IPF)-related aging of lung cells that play a key role in tissue repair, according to a study in a mouse model of IPF.
Notably, these benefits were associated with a normalization of the levels of molecules involved in energy metabolism.
The findings shed light on the molecular and cellular mechanisms behind MSCs’ previously reported benefits in IPF animal models, and highlight the importance of maintaining energetic balance to prevent aging, or senescence, of alveolar type 2 cells, the researchers noted.
The study, “Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT-mediated NAD metabolism,” was published in the journal Stem Cell Research & Therapy.
Treatment with MSCs — stem cells that can generate a variety of other cell types — has shown potential to ease IPF in several animal models.
Their benefits are thought to be associated with their ability to transform into local cell types, suppress the production of molecules involved in scarring (fibrosis), and promote anti-inflammatory and immunoregulatory effects.
However, “the mechanisms underlying the therapeutic effects of MSCs in IPF, especially in terms of alveolar type 2 (AT2) cells senescence, are not well understood,” the researchers wrote.
AT2 cells, one of the cell types that line the small air sacs responsible for gas exchange in the lungs, are involved in lung tissue repair and regeneration. AT2 cell senescence, which is thought to impede the repair of air sacs’ lining, is increasingly considered a key contributing factor to the development and progression of IPF.
Now, a team of researchers at the Sun Yat-sen University, in China, evaluated the effects of human bone marrow-derived MSCs in AT2 cells’ senescence in a mouse model of IPF and in lab-grown mouse AT2 cells.
After treating healthy mice with the anti-cancer medication bleomycin to trigger the onset of IPF, researchers injected either MSCs or a saline solution into the animals’ bloodstream.
Results showed that, consistent with previous reports, MSC treatment significantly reduced lung fibrosis and the levels of pro-fibrotic molecules, and improved animals’ survival relative to the saline solution.
When looking at AT2 cells collected from both mice groups, the team found that MSCs significantly reduced several senescence markers and pro-inflammatory molecules typically produced by senescent, or aged, cells to levels closer to those seen in cells from healthy mice.
Similar results were obtained when MSCs were added to lab-grown mouse AT2 cells exposed to bleomycin.
Further analyses revealed that MSCs’ anti-senescence effects were driven at least partly by a restoration of the levels of nicotinamide phosphoribosyltransferase (NAMPT).
NAMPT is an enzyme involved in the maintenance of cellular energy balance by increasing the levels of nicotinamide adenine dinucleotide (NAD+), a central molecule in energy metabolism.
Particularly, NAMPT and NAD+ levels were reduced significantly in AT2 cells from mice given the saline solution relative to those from healthy mice, suggesting that these cells’ senescence is linked to energy deficits. In turn, AT2 cells from MSC-treated mice showed a nearly normalization of NAMPT and NAD+ levels.
The team also found that these MSC-induced higher NAMPT levels were associated with a suppression of NAMPT breakdown inside lysosomes, the cell’s recycling factories, rather than an increase in the enzyme’s production.
These findings “delineate the novel mechanisms of MSCs protection in animal models of chronic interstitial lung disease,” the researchers wrote.
Of note, interstitial lung disease comprises a group of conditions, including IPF, that are characterized by inflammation and scarring of the tissue and space around the air sacs.
Particularly, the data demonstrate that MSCs “attenuate experimental pulmonary fibrosis through reducing AT2 cells senescence,” and that this is achieved by “suppressing lysosome-mediated NAMPT protein degradation,” the team wrote.
“Our findings highlight the importance of the NAMPT-mediated NAD+ [balance] which may be responsible for the ability of MSCs to control chronic interstitial lung disorders,” they added.
More studies are needed to investigate whether NAMPT is involved in IPF-associated processes in other cell populations and whether MSCs “influence NAD metabolism and NAMPT protein levels in other cell types,” the researchers wrote.
Further research also should focus on how MSCs regulate NAMPT breakdown inside lysosomes, they added.