Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells
Summary: The effects of ascorbate on adult cell fate specification remain largely unknown. Using our stepwise and chemically defined system to derive lateral mesoderm progenitors from human pluripotent stem cells (hPSCs), we found that ascorbate increased the expression of mesenchymal stromal cell (...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671120300023 |
| _version_ | 1828735249414094848 |
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| author | Tong Ming Liu Ege Deniz Yildirim Pin Li Hai Tong Fang Vinitha Denslin Vibhor Kumar Yuin Han Loh Eng Hin Lee Simon M. Cool Bin Tean Teh James H. Hui Bing Lim Ng Shyh-Chang |
| author_facet | Tong Ming Liu Ege Deniz Yildirim Pin Li Hai Tong Fang Vinitha Denslin Vibhor Kumar Yuin Han Loh Eng Hin Lee Simon M. Cool Bin Tean Teh James H. Hui Bing Lim Ng Shyh-Chang |
| author_sort | Tong Ming Liu |
| collection | DOAJ |
| description | Summary: The effects of ascorbate on adult cell fate specification remain largely unknown. Using our stepwise and chemically defined system to derive lateral mesoderm progenitors from human pluripotent stem cells (hPSCs), we found that ascorbate increased the expression of mesenchymal stromal cell (MSC) markers, purity of MSCs, the long-term self-renewal and osteochondrogenic capacity of hPSC-MSCs in vitro. Moreover, ascorbate promoted MSC specification in an iron-dependent fashion, but not in a redox-dependent manner. Further studies revealed that iron synergized with ascorbate to regulate hPSC-MSC histone methylation, promote their long-term self-renewal, and increase their osteochondrogenic capacity. We found that one of the histone demethylases affected by ascorbate, KDM4B, was necessary to promote the specification of hPSC-MSCs. This mechanistic understanding led to the metabolic optimization of hPSC-MSCs with an extended lifespan in vitro and the ability to fully repair cartilage defects upon transplantation in vivo. Our results highlight the importance of ascorbate and iron metabolism in adult human cell fate specification. : In this article, Liu and colleagues show a stepwise protocol for generating human skeletal MSCs from hPSCs via primitive streak and mesoderm. They show that ascorbate promotes the specification of hPSC-MSCs through ascorbate/ion-dependent dioxygenase. They report ascorbate promotes chondrogenesis of hPSC-MSCs which can fully repair cartilage defects. Keywords: human pluripotent stem cells, mesenchymal stem cells, differentiation, cartilage, gene expression profile, ChIP-seq |
| first_indexed | 2024-04-12T23:03:21Z |
| format | Article |
| id | doaj.art-4d9d3e38c78343fd95dc58634ee62cac |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-04-12T23:03:21Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-4d9d3e38c78343fd95dc58634ee62cac2022-12-22T03:12:59ZengElsevierStem Cell Reports2213-67112020-02-01142210225Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal CellsTong Ming Liu0Ege Deniz Yildirim1Pin Li2Hai Tong Fang3Vinitha Denslin4Vibhor Kumar5Yuin Han Loh6Eng Hin Lee7Simon M. Cool8Bin Tean Teh9James H. Hui10Bing Lim11Ng Shyh-Chang12Cancer Stem Cell Group, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Singapore 138672, Singapore; Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673, Singapore; Glycotherapeutics Group, Institute of Medical Biology, Agency for Science Technology and Research, Singapore 138648, Singapore; Corresponding authorCancer Stem Cell Group, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Singapore 138672, SingaporeCancer Stem Cell Group, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Singapore 138672, SingaporeEpigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673, SingaporeDepartment of Orthopaedic Surgery, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, Singapore; NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, SingaporeComputational and Systems Biology Group, Genome Institute of Singapore, A∗STAR, Singapore 138672, SingaporeEpigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673, SingaporeDepartment of Orthopaedic Surgery, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, Singapore; NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, SingaporeGlycotherapeutics Group, Institute of Medical Biology, Agency for Science Technology and Research, Singapore 138648, SingaporeInstitute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673, SingaporeDepartment of Orthopaedic Surgery, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, Singapore; NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Lower Kent Ridge Road, Singapore 119260, SingaporeCancer Stem Cell Group, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Singapore 138672, SingaporeState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China; Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Corresponding authorSummary: The effects of ascorbate on adult cell fate specification remain largely unknown. Using our stepwise and chemically defined system to derive lateral mesoderm progenitors from human pluripotent stem cells (hPSCs), we found that ascorbate increased the expression of mesenchymal stromal cell (MSC) markers, purity of MSCs, the long-term self-renewal and osteochondrogenic capacity of hPSC-MSCs in vitro. Moreover, ascorbate promoted MSC specification in an iron-dependent fashion, but not in a redox-dependent manner. Further studies revealed that iron synergized with ascorbate to regulate hPSC-MSC histone methylation, promote their long-term self-renewal, and increase their osteochondrogenic capacity. We found that one of the histone demethylases affected by ascorbate, KDM4B, was necessary to promote the specification of hPSC-MSCs. This mechanistic understanding led to the metabolic optimization of hPSC-MSCs with an extended lifespan in vitro and the ability to fully repair cartilage defects upon transplantation in vivo. Our results highlight the importance of ascorbate and iron metabolism in adult human cell fate specification. : In this article, Liu and colleagues show a stepwise protocol for generating human skeletal MSCs from hPSCs via primitive streak and mesoderm. They show that ascorbate promotes the specification of hPSC-MSCs through ascorbate/ion-dependent dioxygenase. They report ascorbate promotes chondrogenesis of hPSC-MSCs which can fully repair cartilage defects. Keywords: human pluripotent stem cells, mesenchymal stem cells, differentiation, cartilage, gene expression profile, ChIP-seqhttp://www.sciencedirect.com/science/article/pii/S2213671120300023 |
| spellingShingle | Tong Ming Liu Ege Deniz Yildirim Pin Li Hai Tong Fang Vinitha Denslin Vibhor Kumar Yuin Han Loh Eng Hin Lee Simon M. Cool Bin Tean Teh James H. Hui Bing Lim Ng Shyh-Chang Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells Stem Cell Reports |
| title | Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells |
| title_full | Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells |
| title_fullStr | Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells |
| title_full_unstemmed | Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells |
| title_short | Ascorbate and Iron Are Required for the Specification and Long-Term Self-Renewal of Human Skeletal Mesenchymal Stromal Cells |
| title_sort | ascorbate and iron are required for the specification and long term self renewal of human skeletal mesenchymal stromal cells |
| url | http://www.sciencedirect.com/science/article/pii/S2213671120300023 |
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