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Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications.<\/jats:p>","DOI":"10.3390\/cells12212565","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T09:16:21Z","timestamp":1698916581000},"page":"2565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Treating Parkinson\u2019s Disease with Human Bone Marrow Mesenchymal Stem Cell Secretome: A Translational Investigation Using Human Brain Organoids and Different Routes of In Vivo Administration"],"prefix":"10.3390","volume":"12","author":[{"given":"B\u00e1rbara","family":"Mendes-Pinheiro","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de 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Portugal"}]},{"given":"Carina","family":"Soares-Cunha","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Sarah L.","family":"Nickels","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems and Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg"}]},{"given":"Anna S.","family":"Monzel","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems and Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8273-1055","authenticated-orcid":false,"given":"Jorge R.","family":"Cibr\u00e3o","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Eduardo","family":"Loureiro-Campos","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Sofia C.","family":"Serra","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1858-4318","authenticated-orcid":false,"given":"Sandra","family":"Barata-Antunes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9680-4027","authenticated-orcid":false,"given":"Sara","family":"Duarte-Silva","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7724-0446","authenticated-orcid":false,"given":"Lu\u00edsa","family":"Pinto","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government 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Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s Disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_3","first-page":"129","article-title":"Pharmacological Treatment of Parkinson\u2019s Disease","volume":"Volume 311","author":"Zahoor","year":"2018","journal-title":"Parkinson\u2019s Disease: Pathogenesis and Clinical Aspects"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"862","DOI":"10.12688\/f1000research.25634.1","article-title":"Recent Developments in the Treatment of Parkinson\u2019s Disease","volume":"9","author":"Stoker","year":"2020","journal-title":"F1000Research"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Han, Y., Li, X., Zhang, Y., Han, Y., Chang, F., and Ding, J. (2019). Mesenchymal Stem Cells for Regenerative Medicine. 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