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Transplanted human striatal progenitors exhibit functional integration and modulate host circuitry in a Huntington's disease animal model

Scaramuzza, Linda ; Ribodino, Marta LU ; Cassarino, Christian ; Morrocchi, Marta ; Gomez Gonzalez, Gabriela B. ; Parolisi, Roberta ; Sozzi, Edoardo LU orcid ; Turrini, Giacomo ; Cerrato, Valentina and Conforti, Paola , et al. (2025) In Pharmacological Research 219.
Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. This leads to progressive loss of striatal neurons and motor-cognitive decline. While current gene-targeting approaches aiming at reducing somatic instability show promise – especially in case of early treatment – they cannot restore the already compromised neuronal circuitry at advanced disease stages. Thus, cell replacement therapy offers a regenerative strategy to rebuild damaged striatal circuits. Here, we report that human striatal progenitors (hSPs) derived from embryonic stem cells via a morphogen-guided protocol survive long-term when transplanted into a rodent model of HD and recapitulate key aspects of ventral... (More)

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. This leads to progressive loss of striatal neurons and motor-cognitive decline. While current gene-targeting approaches aiming at reducing somatic instability show promise – especially in case of early treatment – they cannot restore the already compromised neuronal circuitry at advanced disease stages. Thus, cell replacement therapy offers a regenerative strategy to rebuild damaged striatal circuits. Here, we report that human striatal progenitors (hSPs) derived from embryonic stem cells via a morphogen-guided protocol survive long-term when transplanted into a rodent model of HD and recapitulate key aspects of ventral telencephalic development. By employing single-nucleus RNAseq of the grafted cells, we resolved their transcriptional profile with unprecedented resolution. This has identified transcriptional signals of D1- and D2-type medium spiny neurons (MSN), Medial Ganglionic Eminence (MGE) and Caudal Ganglionic Eminence (CGE) -derived interneurons, and regionally specified astrocytes. Moreover, we demonstrate that grafted cells undergo further maturation 6 months post-transplantation, acquiring the expected regionally defined transcriptional identity. Immunohistochemistry confirmed stable graft composition over time and supported a neurogenic-to-gliogenic switch post-transplantation. Multiple complementary techniques including virus-based tracing and electrophysiology assays demonstrated anatomical and functional integration of the grafts. Notably, chemogenetic modulation of graft activity regulated striatal-dependent behaviors, further supporting effective graft integration into host basal ganglia circuits. Altogether, these results provide preclinical evidence that hSP-grafts can reconstruct striatal circuits and modulate functionally relevant behaviors. The ability to generate a scalable, molecularly defined progenitor population capable of in vivo functional integration supports the potential of hSPs for clinical application in HD and related basal ganglia disorders.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell transplantation, Huntington's disease, MSN (Medium Spiny Neurons), Neurodegeneration, Stem cell therapy, Striatum
in
Pharmacological Research
volume
219
article number
107905
publisher
Academic Press
external identifiers
  • scopus:105013196673
  • pmid:40796049
ISSN
1043-6618
DOI
10.1016/j.phrs.2025.107905
language
English
LU publication?
yes
id
a79e4415-eb19-40f5-92a4-e947411ccc34
date added to LUP
2025-10-20 12:05:56
date last changed
2025-10-21 03:28:17
@article{a79e4415-eb19-40f5-92a4-e947411ccc34,
  abstract     = {{<p>Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. This leads to progressive loss of striatal neurons and motor-cognitive decline. While current gene-targeting approaches aiming at reducing somatic instability show promise – especially in case of early treatment – they cannot restore the already compromised neuronal circuitry at advanced disease stages. Thus, cell replacement therapy offers a regenerative strategy to rebuild damaged striatal circuits. Here, we report that human striatal progenitors (hSPs) derived from embryonic stem cells via a morphogen-guided protocol survive long-term when transplanted into a rodent model of HD and recapitulate key aspects of ventral telencephalic development. By employing single-nucleus RNAseq of the grafted cells, we resolved their transcriptional profile with unprecedented resolution. This has identified transcriptional signals of D1- and D2-type medium spiny neurons (MSN), Medial Ganglionic Eminence (MGE) and Caudal Ganglionic Eminence (CGE) -derived interneurons, and regionally specified astrocytes. Moreover, we demonstrate that grafted cells undergo further maturation 6 months post-transplantation, acquiring the expected regionally defined transcriptional identity. Immunohistochemistry confirmed stable graft composition over time and supported a neurogenic-to-gliogenic switch post-transplantation. Multiple complementary techniques including virus-based tracing and electrophysiology assays demonstrated anatomical and functional integration of the grafts. Notably, chemogenetic modulation of graft activity regulated striatal-dependent behaviors, further supporting effective graft integration into host basal ganglia circuits. Altogether, these results provide preclinical evidence that hSP-grafts can reconstruct striatal circuits and modulate functionally relevant behaviors. The ability to generate a scalable, molecularly defined progenitor population capable of in vivo functional integration supports the potential of hSPs for clinical application in HD and related basal ganglia disorders.</p>}},
  author       = {{Scaramuzza, Linda and Ribodino, Marta and Cassarino, Christian and Morrocchi, Marta and Gomez Gonzalez, Gabriela B. and Parolisi, Roberta and Sozzi, Edoardo and Turrini, Giacomo and Cerrato, Valentina and Conforti, Paola and Hoxha, Eriola and Tognato, Riccardo and Galeotti, Greta and Cordiglieri, Chiara and Crosti, Maria Cristina and Zucca, Stefano and Lorenzati, Martina and Bovetti, Serena and Spaiardi, Paolo and de'Sperati, Claudio and Biella, Gerardo and Ottoboni, Linda and Parmar, Malin and Maestri, Simone and Besusso, Dario and Cattaneo, Elena and Buffo, Annalisa}},
  issn         = {{1043-6618}},
  keywords     = {{Cell transplantation; Huntington's disease; MSN (Medium Spiny Neurons); Neurodegeneration; Stem cell therapy; Striatum}},
  language     = {{eng}},
  publisher    = {{Academic Press}},
  series       = {{Pharmacological Research}},
  title        = {{Transplanted human striatal progenitors exhibit functional integration and modulate host circuitry in a Huntington's disease animal model}},
  url          = {{http://dx.doi.org/10.1016/j.phrs.2025.107905}},
  doi          = {{10.1016/j.phrs.2025.107905}},
  volume       = {{219}},
  year         = {{2025}},
}