hESC-derived striatal progenitors grafted into a Huntington’s disease rat model support long-term functional motor recovery by differentiating, self-organizing and connecting into the lesioned striatum
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Published:2023-07-28
Issue:1
Volume:14
Page:
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ISSN:1757-6512
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Container-title:Stem Cell Research & Therapy
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language:en
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Short-container-title:Stem Cell Res Ther
Author:
Schellino Roberta, Besusso Dario, Parolisi Roberta, Gómez-González Gabriela B., Dallere Sveva, Scaramuzza Linda, Ribodino Marta, Campus Ilaria, Conforti Paola, Parmar Malin, Boido Marina, Cattaneo Elena, Buffo AnnalisaORCID
Abstract
Abstract
Background
Huntington’s disease (HD) is a motor and cognitive neurodegenerative disorder due to prominent loss of striatal medium spiny neurons (MSNs). Cell replacement using human embryonic stem cells (hESCs) derivatives may offer new therapeutic opportunities to replace degenerated neurons and repair damaged circuits.
Methods
With the aim to develop effective cell replacement for HD, we assessed the long-term therapeutic value of hESC-derived striatal progenitors by grafting the cells into the striatum of a preclinical model of HD [i.e., adult immunodeficient rats in which the striatum was lesioned by monolateral injection of quinolinic acid (QA)]. We examined the survival, maturation, self-organization and integration of the graft as well as its impact on lesion-dependent motor alterations up to 6 months post-graft. Moreover, we tested whether exposing a cohort of QA-lesioned animals to environmental enrichment (EE) could improve graft integration and function.
Results
Human striatal progenitors survived up to 6 months after transplantation and showed morphological and neurochemical features typical of human MSNs. Donor-derived interneurons were also detected. Grafts wired in both local and long-range striatal circuits, formed domains suggestive of distinct ganglionic eminence territories and displayed emerging striosome features. Moreover, over time grafts improved complex motor performances affected by QA. EE selectively increased cell differentiation into MSN phenotype and promoted host-to-graft connectivity. However, when combined to the graft, the EE paradigm used in this study was insufficient to produce an additive effect on task execution.
Conclusions
The data support the long-term therapeutic potential of ESC-derived human striatal progenitor grafts for the replacement of degenerated striatal neurons in HD and suggest that EE can effectively accelerate the maturation and promote the integration of human striatal cells.
Funder
FP7 Science in Society Università degli Studi di Torino
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Biochemistry, Genetics and Molecular Biology (miscellaneous),Molecular Medicine,Medicine (miscellaneous)
Reference62 articles.
1. Vonsattel JP, Keller C, Del Pilar Amaya M. Neuropathology of Huntington’s disease. Handb Clin Neurol. 2008;89:599–618. 2. Tabrizi SJ, Ghosh R, Leavitt BR. huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron. 2019;102(4):899 (Erratum for: Neuron. 2019;101(5):801–819). 3. Zeitler B, Froelich S, Marlen K, Shivak DA, Yu Q, Li D, Pearl JR, Miller JC, Zhang L, Paschon DE, Hinkley SJ, Ankoudinova I, Lam S, Guschin D, Kopan L, Cherone JM, Nguyen HB, Qiao G, Ataei Y, Mendel MC, Amora R, Surosky R, Laganiere J, Vu BJ, Narayanan A, Sedaghat Y, Tillack K, Thiede C, Gärtner A, Kwak S, Bard J, Mrzljak L, Park L, Heikkinen T, Lehtimäki KK, Svedberg MM, Häggkvist J, Tari L, Tóth M, Varrone A, Halldin C, Kudwa AE, Ramboz S, Day M, Kondapalli J, Surmeier DJ, Urnov FD, Gregory PD, Rebar EJ, Muñoz-Sanjuán I, Zhang HS. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat Med. 2019;25(7):1131–42. 4. Kingwell K. Double setback for ASO trials in Huntington disease. Nat Rev Drug Discov. 2021;20(6):412–3. 5. Grade S, Götz M. Neuronal replacement therapy: previous achievements and challenges ahead. NPJ Regen Med. 2017;2:29.
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