Intracerebral Transplantation of Differentiated Human Embryonic Stem Cells to Hemiparkinsonian Monkeys

Abstract

To explore stem cell therapy for Parkinson’s disease (PD), three adult rhesus monkeys were first rendered hemiparkinsonian by unilateral intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion. Five months postinfusion, they were given MRI-guided stereotaxic intrastriatal and intranigral injections of green fluorescent protein (GFP)-labeled cultures of dopaminergic neurons derived from human embryonic stem cells (DA-hES cells). The animals were immunosuppressed using daily oral cyclosporine (CsA). Three months later, viable grafts were observed at the injection sites in one animal, while no obvious grafts were present in the other two monkeys. The surviving grafts contained numerous GFP-positive cells that were positively labeled for nestin and MAP2 but not for glial fibrillary acidic protein (GFAP), NeuN, or tyrosine hydroxylase (TH). The grafted areas in all animals showed dense staining for GFAP, CD68, and CD45. These results indicated that xenografts of human stem cell derivatives in CsA-suppressed rhesus brain were mostly rejected. Our study suggests that immunological issues are obstacles for preclinical evaluation of hES cells and that improved immunosuppression paradigms and/or alternative cell sources that do not elicit immune rejection are needed for long-term preclinical studies.

Human induced pluripotent stem cell–derived neurons improve motor asymmetry in a 6-hydroxydopamine–induced rat model of Parkinson's disease

“…However, these cell sources are allogenic and may incur immune rejection. In addition, the use of human embryos or fetal central nervous system tissue may give rise to ethical concerns when they are used in clinical practices for PD [14,15]. The generation of induced pluripotent stem cells (iPS cells) through somatic cell reprogramming provides great promise to patients with neurodegenerative diseases such as PD because the iPS cells can be generated from autologous cells and are able to overcome the barriers of allogenic cell transplantation [16e20].…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…Emborg and collaborators (2013) implanted iPSCs in the anterior and posterior parts of CdN; in the anterior, mid-and posterior parts of Put; and in SN (2.5-5 × 10 5 cells per site) of hemiparkinsonian rhesus monkeys 12 to 18 months following MPTP intoxication by intracarotid infusion (Emborg et al, 2013b). There was no obvious behavioral recovery and no PET change (data not shown) following transplantation.…”

“…These recent studies suggest that immunosuppression can only be withdrawn in the autologous models (Emborg et al, 2013b;Morizane et al, 2013;Sundberg et al, 2013). Direct comparison of autograft and allografts in the lesioned NHP brain might ultimately confirm the efficacy and safety of autologous iPSC-derived or iDA cells.…”

“…Although these methods enabled efficient DA differentiation, the cultures usually comprise a high percentage of glial cells and multiple neuron subtypes, such as GABAergic, cholinergic and serotonergic neurons (Emborg et al, 2013b;Morizane et al, 2013). Complete and robust midbrain specification was recently obtained via a floor plate intermediate stage from human (Kriks et al, 2011;Xi et al, 2012;Sundberg et al, 2013) and NHP PSCs (Xi et al, 2012;Hallett et al, 2015;Wang et al, 2015), using a modified dual-SMAD inhibition protocol (BMP/TGFβ inhibition; Chambers et al, 2009) and activation of Wnt signalling, an essential pathway in DA neuron development in the mouse (Castelo-Branco et al, 2003Joksimovic et al, 2009) and in humans (La Manno et al, 2016).…”

Paracrine Effects of Mesenchymal Stem Cells-Conditioned Medium on Microglial Cytokines Expression and Nitric Oxide Production

“…Several studies have demonstrated the immunomodulatory effects of MSC on microglial in coculture systems involving cell-cell interactions [15,17,18]. However, there are more obstacles and complex effects produced with cell transplantation in the CNS than in other parts of the body [19,20]. This study was initiated to determine the paracrine effects of MSC using MSC-conditioned medium (MSC-CM) in modulating microglial activities in vitro.…”