Functional Rescue of Dopaminergic Neuron Loss in Parkinson's Disease Mice After Transplantation of Hematopoietic Stem and Progenitor Cells

• Published in: EBioMedicine 2016-06, Vol.8 (C), p.83-95
• Main Authors: Altarche-Xifro, Wassim, di Vicino, Umberto, Muñoz-Martin, Maria Isabel, Bortolozzi, Analía, Bové, Jordi, Vila, Miquel, Cosma, Maria Pia
• Format: Article
• Language: English
• Subjects: Animals; Astroglia; Cell Count; Cell Fusion; Cell Survival; Cellular Reprogramming; Disease Models, Animal; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Hematopoietic stem and progenitor cells; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hybrid Cells; Intracerebral transplantation; Male; Mice; Neurodegenerative disorder; Neuroglia - metabolism; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson's disease; Research Paper; Substantia Nigra - metabolism; Substantia Nigra - pathology; Wnt Signaling Pathway; Wnt/β-catenin
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.04.016

Parkinson's disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinson's disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinson's disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinson's disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach. [Display omitted] •Transplantation of HSPCs into the substantia nigra of PD mice ameliorates dopaminergic neuron loss and function.•Hybrids generated after fusion of transplanted HSPCs undergo reprogramming in vivo and acquire features of mature astroglia.•Newly generated astroglia produced Wnt1 and can functionally rescue the dopaminergic neuron loss. A definitive therapy for Parkinson's disease is not available. Here, we transplanted hematopoietic stem and progenitor cells into the substantia nigra of brains of two different mouse models of Parkinson's disease. These transplanted cells fused with neurons and glial cells of the recipient mice. Four weeks after transplantation, the hybrids acquired features of mature astroglia, secreted Wnt1, and functionally ameliorated dopaminergic neuron loss. Current cell therapy approaches are being pursued in the striatum with the aim to increase dopamine levels. Here we show that the loss of dopaminergic neurons can be protected against by direct actions in the substantia nigra.