NDLI: Reprogrammed human lateral ganglionic eminence precursors generate striatal neurons and restore motor function in a rat model of Huntington’s disease

Content Provider	Springer Nature : BioMed Central
Author	McCaughey-Chapman, Amy Burgers, Anne Lieke Combrinck, Catharina Marriott, Laura Gordon, David Connor, Bronwen
Abstract	Background Huntington’s disease (HD) is a genetic neurological disorder predominantly characterised by the progressive loss of GABAergic medium spiny neurons in the striatum resulting in motor dysfunction. One potential strategy for the treatment of HD is the development of cell replacement therapies to restore neuronal circuitry and function by the replacement of lost neurons. We propose the generation of lineage-specific human lateral ganglionic eminence precursors (hiLGEP) using direct reprogramming technology provides a novel and clinically viable cell source for cell replacement therapy for HD. Methods hiLGEPs were derived by direct reprogramming of adult human dermal fibroblasts (aHDFs) using chemically modified mRNA (cmRNA) and a defined reprogramming medium. hiLGEPs were differentiated in vitro using an optimised striatal differentiation medium. Acquisition of a striatal precursor and neural cell fate was assessed through gene expression and immunocytochemical analysis of key markers. hiLGEP-derived striatal neuron functionality in vitro was demonstrated by calcium imaging using Cal-520. To investigate the ability for hiLGEP to survive, differentiate and functionally integrate in vivo, we transplanted hiLGEPs into the striatum of quinolinic acid (QA)-lesioned rats and performed behavioural assessment using the cylinder test over the course of 14 weeks. Survival and differentiation of hiLGEPs was assessed at 8 and 14-weeks post-transplant by immunohistochemical analysis. Results We demonstrate the capability to generate hiLGEPs from aHDFs using cmRNA encoding the pro-neural genes SOX2 and PAX6, combined with a reprogramming medium containing Gö6983, Y-27,632, N-2 and Activin A. hiLGEPs generated functional DARPP32 + neurons following 14 days of culture in BrainPhys™ media supplemented with dorsomorphin and Activin A. We investigated the ability for hiLGEPs to survive transplantation, differentiate to medium spiny-like striatal neurons and improve motor function in the QA lesion rat model of HD. Fourteen weeks after transplantation, we observed STEM121 + neurons co-expressing MAP2, DARPP32, GAD65/67, or GABA. Rats transplanted with hiLGEPs also demonstrated reduction in motor function impairment as determined by spontaneous exploratory forelimb use when compared to saline transplanted animals. Conclusion This study provides proof-of-concept and demonstrates for the first time that aHDFs can be directly reprogrammed to hiLGEPs which survive transplantation, undergo neuronal differentiation to generate medium spiny-like striatal neurons, and reduce functional impairment in the QA lesion rat model of HD.
Related Links	https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-024-04057-9.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
ISSN	17576512
DOI	10.1186/s13287-024-04057-9
Journal	Stem Cell Research & Therapy
Issue Number	1
Volume Number	15
Language	English
Publisher	BioMed Central
Publisher Date	2024-11-22
Access Restriction	Open
Subject Keyword	Stem Cells Cell Biology Regenerative Medicine Tissue Engineering Biomedical Engineering and Bioengineering Huntington’s disease Lateral ganglionic eminence precursor cells Striatum Direct reprogramming Cell replacement therapy Regenerative Medicine/Tissue Engineering
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Biochemistry, Genetics and Molecular Biology Molecular Medicine
Journal Impact Factor	7.1/2023
5-Year Journal Impact Factor	7.9/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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

Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells

How to make striatal projection neurons.

Cardiomyocyte precursors generated by direct reprogramming and molecular beacon selection attenuate ventricular remodeling after experimental myocardial infarction

Directly induced human Schwann cell precursors as a valuable source of Schwann cells

Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

Silencing of hepatic fate-conversion factors induce tumorigenesis in reprogrammed hepatic progenitor-like cells

Generation of striatal neurons from human induced pluripotent stem cells by controlling extrinsic signals with small molecules

Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells

Reprogrammed human lateral ganglionic eminence precursors generate striatal neurons and restore motor function in a rat model of Huntington’s disease

Similar Documents

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

Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells

How to make striatal projection neurons.

Cardiomyocyte precursors generated by direct reprogramming and molecular beacon selection attenuate ventricular remodeling after experimental myocardial infarction

Directly induced human Schwann cell precursors as a valuable source of Schwann cells

Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

Silencing of hepatic fate-conversion factors induce tumorigenesis in reprogrammed hepatic progenitor-like cells

Generation of striatal neurons from human induced pluripotent stem cells by controlling extrinsic signals with small molecules

Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells

Reprogrammed human lateral ganglionic eminence precursors generate striatal neurons and restore motor function in a rat model of Huntington’s disease