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

Abstract

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 4 weeks 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. ; We are grateful for the support from a Fundació La Marató de TV3 grant (120530 to M.P.C. and M.V.), an ERC grant (242630-RERE to M.P.C.), Ministerio de Ciencia e Inovación grants (SAF2011-28580, 2014SGR1137 and BFU2015-71984-ERC to M.P.C.), an AGAUR grant (2014 SGR 780 to M.P.C.), Fondo de Investigación Sanitaria-Instituto de Salud Carlos III grants (PI13/01897 to M.V.; CP11/00229 to J.B.), an AGAUR-GRC grant (2014-SGR-1609 to M.V.), European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Intra-European Fellowship (274882 to W.A.X) and Juan de la Cierva fellowship (to W.A.X), Spanish Ministry of Economy and Competitiveness,'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208.