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However, the osteogenic differentiation capacity of these cells remains inconsistent and could be improved to achieve greater efficiency. Although metformin, a widely used oral hypoglycemic agent, has been shown to increase bone formation in various cell types, its effect on osteogenic differentiation of PL-MSCs has not yet been investigated. Therefore, the objective of this study was to examine the effect of metformin on the osteogenic differentiation capacity of PL-MSCs and the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The PL-MSCs were treated with 0.5 to 640\u00a0\u00b5M metformin and their osteogenic differentiation capacity was examined by an alkaline phosphatase (ALP) activity assay, Alizarin red S staining and expression levels of osteogenic genes. The role of adenosine 5\u2032-monophosphate-activated protein kinase (AMPK) signaling in mediating the effect of metformin on the osteogenic differentiation capacity of PL-MSCs was also investigated by determining levels of phosphorylated AMPK\u00a0(pAMPK)\/AMPK ratio and by using compound C, an AMPK inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The results showed that 10\u2013160\u00a0\u00b5M metformin significantly increased the viability of PL-MSCs in a dose- and time-dependent manner. Furthermore, 80\u2013320\u00a0\u00b5M metformin also increased ALP activity, matrix mineralization, and expression levels of osteogenic genes, runt-related transcription factor 2 (\n                      <jats:italic>RUNX2<\/jats:italic>\n                      ), osterix (\n                      <jats:italic>OSX<\/jats:italic>\n                      ), osteocalcin (\n                      <jats:italic>OCN<\/jats:italic>\n                      ) and collagen I (\n                      <jats:italic>COL1<\/jats:italic>\n                      ), in PL-MSCs. Metformin increases osteogenic differentiation of PL-MSCs, at least in part, through the AMPK signaling pathway, since the administration of compound C inhibited its enhancing effects on ALP activity, matrix mineralization, and osteogenic gene expression of PL-MSCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated that metformin at concentrations of 80\u2013320\u00a0\u03bcM significantly enhanced osteogenic differentiation of PL-MSCs in a dose- and time-dependent manner, primarily through activation of the AMPK signaling pathway. This finding suggests that metformin could be used with other conventional drugs to induce bone regeneration in various bone diseases. Additionally, this study provides valuable insights for future osteoporosis treatment by highlighting the potential of modulating the AMPK pathway to improve bone regeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-024-04014-6","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T19:12:36Z","timestamp":1731438756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Improvement of osteogenic differentiation potential of placenta-derived mesenchymal stem cells by metformin via AMPK pathway activation"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0565-3441","authenticated-orcid":false,"given":"Sirikul","family":"Manochantr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ladda","family":"Meesuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuengruethai","family":"Chadee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintamai","family":"Suwanprateeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chairat","family":"Tantrawatpan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pakpoom","family":"Kheolamai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"issue":"2","key":"4014_CR1","doi-asserted-by":"publisher","first-page":"360","DOI":"10.3390\/ijms19020360","volume":"19","author":"L Hu","year":"2018","unstructured":"Hu L, Yin C, Zhao F, Ali A, Ma J, Qian A. 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J Mater Sci Mater Med. 2015;26(11):254.","journal-title":"J Mater Sci Mater Med"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-024-04014-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-024-04014-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-024-04014-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T20:04:28Z","timestamp":1731441868000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-024-04014-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,13]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["4014"],"URL":"https:\/\/doi.org\/10.1186\/s13287-024-04014-6","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,13]]},"assertion":[{"value":"22 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experimental procedures were conducted in accordance with the Declaration of Helsinki and the Belmont report. This study was approved by the Human Research Ethics Committee of Thammasat University (Medicine) [Approval title: Effect of metformin on cell viability and osteogenic differentiation potential of human mesenchymal stem cells.] [Approval number: 037\/2021] (Date of Approval: February 25, 2021). All samples were obtained from donors with their written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"417"}}