Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis
Abstract Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need...
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| Format: | Article |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-52362-3 |
| _version_ | 1797274874916372480 |
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| author | Fabrizio E. Mancini Paul E. A. Humphreys Steven Woods Nicola Bates Sara Cuvertino Julieta O’Flaherty Leela Biant Marco A. N. Domingos Susan J. Kimber |
| author_facet | Fabrizio E. Mancini Paul E. A. Humphreys Steven Woods Nicola Bates Sara Cuvertino Julieta O’Flaherty Leela Biant Marco A. N. Domingos Susan J. Kimber |
| author_sort | Fabrizio E. Mancini |
| collection | DOAJ |
| description | Abstract Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans. |
| first_indexed | 2024-03-07T15:04:24Z |
| format | Article |
| id | doaj.art-7f0785f7ef8b40a899ff7fca232187f7 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:04:24Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-7f0785f7ef8b40a899ff7fca232187f72024-03-05T18:57:54ZengNature PortfolioScientific Reports2045-23222024-02-0114111410.1038/s41598-024-52362-3Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesisFabrizio E. Mancini0Paul E. A. Humphreys1Steven Woods2Nicola Bates3Sara Cuvertino4Julieta O’Flaherty5Leela Biant6Marco A. N. Domingos7Susan J. Kimber8Division of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDivision of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterDepartment of Solids and Structures, School of Engineering, Faculty of Science and Engineering, University of ManchesterDivision of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of ManchesterAbstract Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.https://doi.org/10.1038/s41598-024-52362-3 |
| spellingShingle | Fabrizio E. Mancini Paul E. A. Humphreys Steven Woods Nicola Bates Sara Cuvertino Julieta O’Flaherty Leela Biant Marco A. N. Domingos Susan J. Kimber Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis Scientific Reports |
| title | Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis |
| title_full | Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis |
| title_fullStr | Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis |
| title_full_unstemmed | Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis |
| title_short | Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis |
| title_sort | effect of a retinoic acid analogue on bmp driven pluripotent stem cell chondrogenesis |
| url | https://doi.org/10.1038/s41598-024-52362-3 |
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