Abstract
Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.
Highlights
Aging has been associated with a decline in the function of multiple organs due to degenerative changes in tissue-specific stem cells or stem cell niches, as well as decreased bone metabolism and osteoporosis, which are high-risk factors for bone fractures [1,2].The current and unprecedented super-aging of the population requires urgent adaptation in the health care system worldwide
There are more than 500 amino acids in nature [3,4]; only 22 of them can be found in the human body, which are termed as 22 common amino acids, and include nine essential and 13 non-essential amino acids [5]
Images and graphs are representative of at least three independent experiments. These results suggest that L-kynurenine is the major pathway associated with the effect of L-tryptophan on promoting the increase in stemness and osteogenic ability of BMSCs
Summary
The current and unprecedented super-aging of the population requires urgent adaptation in the health care system worldwide. In this context, preventive approaches focusing on antiaging therapies or the treatment of age-related diseases or dysfunctions have attracted researchers to search for novel management and therapeutic approaches, including stem cell therapy. Amino acids pass through the cell membrane via the amino acid transporter [6], and can be used for protein synthesis, and/or be degraded into one of seven common metabolic intermediates that can be further converted into glucose or oxidized by the citric acid cycle [7]. Amino acids play fundamental roles in processes such as neurotransmitter transport and gene transcription [8]
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