Cargando…

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pham, Hai Thanh, Ono, Mitsuaki, Hara, Emilio Satoshi, Nguyen, Ha Thi Thu, Dang, Anh Tuan, Do, Hang Thuy, Komori, Taishi, Tosa, Ikue, Hazehara-Kunitomo, Yuri, Yoshioka, Yuya, Oida, Yasutaka, Akiyama, Kentaro, Kuboki, Takuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796421/
https://www.ncbi.nlm.nih.gov/pubmed/33406724
http://dx.doi.org/10.3390/ma14010208
_version_ 1783634678092136448
author Pham, Hai Thanh
Ono, Mitsuaki
Hara, Emilio Satoshi
Nguyen, Ha Thi Thu
Dang, Anh Tuan
Do, Hang Thuy
Komori, Taishi
Tosa, Ikue
Hazehara-Kunitomo, Yuri
Yoshioka, Yuya
Oida, Yasutaka
Akiyama, Kentaro
Kuboki, Takuo
author_facet Pham, Hai Thanh
Ono, Mitsuaki
Hara, Emilio Satoshi
Nguyen, Ha Thi Thu
Dang, Anh Tuan
Do, Hang Thuy
Komori, Taishi
Tosa, Ikue
Hazehara-Kunitomo, Yuri
Yoshioka, Yuya
Oida, Yasutaka
Akiyama, Kentaro
Kuboki, Takuo
author_sort Pham, Hai Thanh
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7796421
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-77964212021-01-10 Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo Pham, Hai Thanh Ono, Mitsuaki Hara, Emilio Satoshi Nguyen, Ha Thi Thu Dang, Anh Tuan Do, Hang Thuy Komori, Taishi Tosa, Ikue Hazehara-Kunitomo, Yuri Yoshioka, Yuya Oida, Yasutaka Akiyama, Kentaro Kuboki, Takuo Materials (Basel) Article 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. MDPI 2021-01-04 /pmc/articles/PMC7796421/ /pubmed/33406724 http://dx.doi.org/10.3390/ma14010208 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pham, Hai Thanh
Ono, Mitsuaki
Hara, Emilio Satoshi
Nguyen, Ha Thi Thu
Dang, Anh Tuan
Do, Hang Thuy
Komori, Taishi
Tosa, Ikue
Hazehara-Kunitomo, Yuri
Yoshioka, Yuya
Oida, Yasutaka
Akiyama, Kentaro
Kuboki, Takuo
Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title_full Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title_fullStr Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title_full_unstemmed Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title_short Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo
title_sort tryptophan and kynurenine enhances the stemness and osteogenic differentiation of bone marrow-derived mesenchymal stromal cells in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796421/
https://www.ncbi.nlm.nih.gov/pubmed/33406724
http://dx.doi.org/10.3390/ma14010208
work_keys_str_mv AT phamhaithanh tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT onomitsuaki tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT haraemiliosatoshi tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT nguyenhathithu tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT danganhtuan tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT dohangthuy tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT komoritaishi tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT tosaikue tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT hazeharakunitomoyuri tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT yoshiokayuya tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT oidayasutaka tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT akiyamakentaro tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo
AT kubokitakuo tryptophanandkynurenineenhancesthestemnessandosteogenicdifferentiationofbonemarrowderivedmesenchymalstromalcellsinvitroandinvivo