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
Schellino, Roberta ; Besusso, Dario ; Parolisi, Roberta ; Gómez-González, Gabriela B. ; Dallere, Sveva ; Scaramuzza, Linda ; Ribodino, Marta LU ; Campus, Ilaria ; Conforti, Paola and Parmar, Malin LU
, et al.
(2023)
In Stem Cell Research and Therapy
14.
p.1-21
- 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... (More)
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.
(Less)
- author
- Schellino, Roberta
; Besusso, Dario
; Parolisi, Roberta
; Gómez-González, Gabriela B.
; Dallere, Sveva
; Scaramuzza, Linda
; Ribodino, Marta
LU
; Campus, Ilaria
; Conforti, Paola
and Parmar, Malin
LU
, et al. (More)
- Schellino, Roberta
; Besusso, Dario
; Parolisi, Roberta
; Gómez-González, Gabriela B.
; Dallere, Sveva
; Scaramuzza, Linda
; Ribodino, Marta
LU
; Campus, Ilaria
; Conforti, Paola
; Parmar, Malin
LU
; Boido, Marina
; Cattaneo, Elena
and Buffo, Annalisa
(Less)
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Direct and indirect pathways, Human embryonic stem cells, In vitro differentiation, Medium spiny neurons, Transplantation, Viral tracing
- in
- Stem Cell Research and Therapy
- volume
- 14
- article number
- 189
- pages
- 1 - 21
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:37507794
- scopus:85165981304
- ISSN
- 1757-6512
- DOI
- 10.1186/s13287-023-03422-4
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2023, The Author(s).
- id
- 3189d944-890a-404e-919b-7e63b791b564
- date added to LUP
- 2023-09-19 14:25:43
- date last changed
- 2024-04-19 01:07:41
@article{3189d944-890a-404e-919b-7e63b791b564,
abstract = {{<p>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.</p>}},
author = {{Schellino, Roberta and Besusso, Dario and Parolisi, Roberta and Gómez-González, Gabriela B. and Dallere, Sveva and Scaramuzza, Linda and Ribodino, Marta and Campus, Ilaria and Conforti, Paola and Parmar, Malin and Boido, Marina and Cattaneo, Elena and Buffo, Annalisa}},
issn = {{1757-6512}},
keywords = {{Direct and indirect pathways; Human embryonic stem cells; In vitro differentiation; Medium spiny neurons; Transplantation; Viral tracing}},
language = {{eng}},
pages = {{1--21}},
publisher = {{BioMed Central (BMC)}},
series = {{Stem Cell Research and Therapy}},
title = {{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}},
url = {{http://dx.doi.org/10.1186/s13287-023-03422-4}},
doi = {{10.1186/s13287-023-03422-4}},
volume = {{14}},
year = {{2023}},
}