{"id":161292,"date":"2023-03-30T10:23:33","date_gmt":"2023-03-30T15:23:33","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2023\/03\/transplantation-of-clinical-grade-human-neural-stem-cells-reduces-neuroinflammation-prolongs-survival-and-delays-disease-progression-in-the-sod1-rats"},"modified":"2023-03-30T10:23:33","modified_gmt":"2023-03-30T15:23:33","slug":"transplantation-of-clinical-grade-human-neural-stem-cells-reduces-neuroinflammation-prolongs-survival-and-delays-disease-progression-in-the-sod1-rats","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2023\/03\/transplantation-of-clinical-grade-human-neural-stem-cells-reduces-neuroinflammation-prolongs-survival-and-delays-disease-progression-in-the-sod1-rats","title":{"rendered":"Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats"},"content":{"rendered":"<p style=\"padding-right: 20px\"><a class=\"aligncenter blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/transplantation-of-clinical-grade-human-neural-stem-cells-reduces-neuroinflammation-prolongs-survival-and-delays-disease-progression-in-the-sod1-rats.jpg\"><\/a><\/p>\n<p>The hNSCs used in the study have been produced and characterised in the Cell Factory and Biobank of Santa Maria Hospital (Terni, Italy), authorised by the Italian Medicine Agency (AIFA) for the production of hNSCs to be used for clinical trials (aM 54\/2018). The methodology applied to isolate, expand, characterise and cryopreserve the lines is based on the Neurosphere Assay<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 26\" title=\"Vescovi, A. L. et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp. Neurol. 156, 71&ndash;83 (1999).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR26\" id=\"ref-link-section-d12536578e1748\">26<\/a>,<a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 41\" title=\"Gelati, M. et al. Culturing and expansion of \u201cclinical grade\u201d precursors cells from the fetal human central nervous system. Methods Mol. Biol. 1,059, 65&ndash;77 (2013).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR41\" id=\"ref-link-section-d12536578e1751\">41<\/a>,<a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 54\" title=\"Gritti, A., Galli, R. & Vescovi, A. Cultures of Stem Cells of the Central Nervous System. Protocols for Neural Cell Culture. (ed Fedoroff, S.), 173&ndash;197, Humana Press: Totowa, NJ, USA (2000).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR54\" id=\"ref-link-section-d12536578e1754\">54<\/a><\/sup>, and has been used for the production of the cells utilised in phase I trials for Amyotrophic Lateral Sclerosis patients (NCT01640067<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 23\" title=\"Mazzini, L. et al. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J. Transl. Med. 13, 17 (2015).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR23\" id=\"ref-link-section-d12536578e1758\">23<\/a><\/sup>) and for Secondary Progressive Multiple Sclerosis patients (NCT03282760, ongoing).<\/p>\n<p>The entire production process, starting from tissue procurement to cryopreservation is compliant to cGMP guidelines and approved by AIFA. The hNSCs are obtained from foetal brain tissue derived from fetuses that underwent miscarriage or natural in utero death upon receiving the signed informed consent from the mother. Forty-eight hours prior to implantation, hNSCs were plated in the growth medium at a concentration of 10,000 cells\/cm<sup>2<\/sup>. On the day of surgery, hNSCs were collected by centrifugation, viable cells were counted by Trypan blue exclusion criteria, and the correct number of cells were re-suspended in HBSS for the transplant.<\/p>\n<p>SOD1 transgenic male rats were randomly divided into three experimental groups: (i) transplanted with hNSCs (hNSC rats, <i>n<\/i> = 15); (ii) treated with HBSS (HBSS rats, <i>n<\/i> = 15) and (iii) untreated (CTRL rats, <i>n<\/i> = 22). An additional group of non-transgenic littermates (wild-type, WT, <i>n<\/i> = 9) were used as controls for symptomatic evaluation of the colony. Tacrolimus (FK506) and cyclosporine (cyclosporin A) are the principal immunosuppressive drugs that have been applied for solid organ transplantation<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 55\" title=\"Kapturczak, M. H., Meier-Kriesche, H. U. & Kaplan, B. Pharmacology of calcineurin antagonists. Transplant. Proc. 36, 25s&ndash;32s (2004).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR55\" id=\"ref-link-section-d12536578e1787\">55<\/a>,<a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 56\" title=\"Williams, D. & Haragsim, L. Calcineurin nephrotoxicity. Adv. Chronic. Kidney. Dis. 13, 47&ndash;55 (2006).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR56\" id=\"ref-link-section-d12536578e1790\">56<\/a><\/sup> and have been translated to stem cell treatments for PD<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 57\" title=\"Kirkeby, A., Parmar, M. & Barker, R. A. Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog. Brain. Res. 230165&ndash;190 (2017).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR57\" id=\"ref-link-section-d12536578e1795\">57<\/a><\/sup> and ALS<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 22\" title=\"Mazzini, L. et al. Advances in stem cell therapy for amyotrophic lateral sclerosis. Expert. Opin. Biol. Ther. 18865&ndash;881 (2018).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR22\" id=\"ref-link-section-d12536578e1799\">22<\/a><\/sup>. In animal models, despite differences in potency, both drugs showed excellent survival rates for grafts across many comparative studies<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 58\" title=\"Maes, B. D. & Vanrenterghem, Y. F. Cyclosporine: advantages versus disadvantages vis-a-vis tacrolimus. Transplant. Proc. 36, 40s&ndash;49s (2004).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR58\" id=\"ref-link-section-d12536578e1803\">58<\/a>,<a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 59\" title=\"Diehl, R. et al. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell. Mol. Immunol. 14146&ndash;179 (2017).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR59\" id=\"ref-link-section-d12536578e1806\">59<\/a><\/sup>. Our previous results<sup><a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 44\" title=\"Rota Nodari, L. et al. Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression. PLoS ONE 5, e14035 (2010).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR44\" id=\"ref-link-section-d12536578e1810\">44<\/a>,<a data-track=\"click\" data-track-action=\"reference anchor\" data-track-label=\"link\" data-test=\"citation-ref\" aria-label=\"Reference 45\" title=\"Ferrari, D. et al. Differential pathotropism of non-immortalized and immortalized human neural stem cell lines in a focal demyelination model. Cell. Mol. Life Sci. 69, 1193&ndash;1210 (2012).\" href=\"https:\/\/www.nature.com\/articles\/s41419-019-1582-5#ref-CR45\" id=\"ref-link-section-d12536578e1813\">45<\/a><\/sup> showed that hNSCs can survive\u2014without signs of rejection\u2014in the rat brain up to 6 months under transient immunosuppression treatment, with cyclosporin A. On the bases of these results, we applied the same immunosuppressive treatment with administration of cyclosporine A (15 mg\/kg\/day subcutaneous; Sandimmne, Novartis) that was initiated on the day of transplantation and continued for 15 days after surgery (for all animal groups).<\/p>\n","protected":false},"excerpt":{"rendered":"<p>The hNSCs used in the study have been produced and characterised in the Cell Factory and Biobank of Santa Maria Hospital (Terni, Italy), authorised by the Italian Medicine Agency (AIFA) for the production of hNSCs to be used for clinical trials (aM 54\/2018). The methodology applied to isolate, expand, characterise and cryopreserve the lines is [\u2026]<\/p>\n","protected":false},"author":661,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,2017,269,47],"tags":[],"class_list":["post-161292","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-cryonics","category-life-extension","category-neuroscience"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/161292","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/661"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=161292"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/161292\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=161292"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=161292"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=161292"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}