Modulation of human induced neural stem cell-derived dopaminergic neurons by DREADD reveals therapeutic effects on a mouse model of Parkinson's disease

• Published in: Stem cell research & therapy Vol. 15; no. 1; pp. 297 - 14
• Main Authors: Wang, Xueyao, Han, Deqiang, Zheng, Tianqi, Ma, Jinghong, Chen, Zhiguo
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.09.2024; BioMed Central; BMC
• Subjects: Analysis; Animals; Apomorphine; Cell Differentiation; Clozapine; Clozapine - analogs & derivatives; Clozapine - pharmacology; Designer receptors exclusively activated by designer drug; Disease Models, Animal; Diseases; Dopaminergic Neurons - metabolism; Health aspects; Humans; Induced neural stem cell; Mice; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neural Stem Cells - transplantation; Neurons; Parkinson Disease - therapy; Parkinson’s disease; Remote modulation; Stem cell therapy; Stem cells; Transplantation; Designer receptors exclusively activated by designer drug; Stem cell therapy; Induced neural stem cell; Remote modulation; Parkinson’s disease
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-024-03921-y

Stem cell-based therapy is a promising strategy for treating Parkinson's disease (PD) characterized by the loss of dopaminergic neurons. Recently, induced neural stem cell-derived dopaminergic precursor cells (iNSC-DAPs) have been emerged as a promising candidate for PD cell therapy because of a lower tumor-formation ability. Designer receptors exclusively activated by designer drugs (DREADDs) are useful tools for examining functional synaptic connections with host neurons. DREADD knock-in human iNSCs to express excitatory hM3Dq and inhibitory hM4Di receptors were engineered by CRISPR. The knock-in iNSCs were differentiated into midbrain dopaminergic precursor cells (DAPs) and transplanted into PD mice. The various behavior test such as the Apomorphine-induced rotation test, Cylinder test, Rotarod test, and Open field test were assessed at 4, 8, or 12 weeks post-transplantation with or without the administration of CNO. Electrophysiology were performed to assess the integrated condition and modulatory function to host neurons. DREADD expressing iNSCs were constructed with normal neural stem cells characteristics, proliferation ability, and differentiation potential into dopaminergic neuorns. DAPs derived from DREADD expressing iNSC showed matched function upon administration of clozapine N-oxide (CNO) in vitro. The results of electrophysiology and behavioral tests of transplanted PD mouse models revealed that the grafts established synaptic connections with downstream host neurons and exhibited excitatory or inhibitory modulation in response to CNO in vivo. iNSC-DAPs are a promising candidate for cell replacement therapy for Parkinson's disease. Remote DREADD-dependent activation of iNSC-DAP neurons significantly enhanced the beneficial effects on transplanted mice with Parkinson's disease.