Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson's disease

Abstract

Realistically, future stem cell therapies for neurological conditions including Parkinson's disease (PD) will most probably entail combination treatment strategies, involving both the stimulation of endogenous cells and transplantation. Therefore, this study investigates these two modes of neural precursor cell (NPC) therapy in concert in order to determine their interrelationships in a rat PD model. Human placental alkaline phosphatase (hPAP) labeled NPCs were transplanted unilaterally into host rats which were subsequently infused ipsilaterally with 6-hydroxydopamine (6-OHDA). The reaction of host NPCs to the transplantation and 6-OHDA was tracked by bromodeoxyuridine labeling. Two weeks after transplantation, in animals transplanted with NPCs, we found evidence of elevated host subventricular zone NPC proliferation, neurogenesis, and migration to the graft site. In these animals, we also observed a significant preservation of striatal tyrosine hydroxylase (TH) expression and substantia nigra TH cell number. We have seen no evidence that neuroprotection is a product of DA neuron replacement by NPC-derived cells. Rather, the NPCs expressed glial cell line-derived neurotrophic factor (GDNF), sonic hedgehog (Shh) and stromal cell derived factor 1 alpha (SDF1α) providing a molecular basis for the observed neuroprotection and endogenous NPC response to transplantation. In summary, our data suggests plausible synergy between exogenous and endogenous NPC actions, and that NPC implantation before the 6-OHDA insult can create a host microenvironment conducive to stimulation of endogenous NPCs, and protection of mature nigral neurons.

Effects of the iron oxide nanoparticle Molday ION Rhodamine B on the viability and regenerative function of neural stem cells: relevance to clinical translation

“…5,17 The expression of hPAP allows identification of grafted NPCs, labeled with this human marker, within the brains of wild-type host rats. 17,18 The NSCs were grown in uncoated dishes in proliferation medium consisting of serum-free Neurobasal-A (Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 20 ng/mL epidermal growth factor (Cell Sciences, Canton, MA, USA), 10 ng/mL basic fibroblast growth factor (Cell Sciences), 2 μg/ mL heparin (STEMCELL Technologies, Vancouver, BC, Canada), 2% B27 (Thermo Fisher Scientific), 1% glutamax (Thermo Fisher Scientific), and 1% antibiotic-antimycotic (Thermo Fisher Scientific).…”

“…Multiple concentrations and times of MIRB treatment (5,10,20,50,60,80, and 100 μg Fe/mL for 18, 20, 30, or 48 hours) were first tested to assess NSC labeling ( Figure S1). These experiments indicated that both 20 and 50 μg doses when applied for 20 hours resulted in optimal labeling of the NSCs as visualized by Prussian blue staining and under rhodamine fluorescence.…”

“…4,5,17 Using these well-characterized cells (Figure 1), we tested several doses of MIRB to determine the optimal concentration and time required for the clear and uniform labeling of NSCs in culture ( Figure S1). MIRB is a commercially available iron oxide nanoparticle, which has been shown to robustly label and support MRI-based tracking of a variety of stem cells.…”

“…[1][2][3][4][5] In fact, clinical trials testing the safety and therapeutic efficacy of NSC transplants in patients with spinal…”

1980-2011: Parkinson's Disease and Advance in Stem Cell Research

“…Presence of neurogenesis in the SNc suggests that disease progression may rely on the loss of dopaminergic neurons as well as on the malfunctioning in their turnover. Possible efficacy of orthotopic dopaminergic neurogenesis in PD has been questioned for a long time (Hermann and Storch, 2008), but transplantation experiments have indicated that several SC types, including neural precursors (Arias-Carrion et al, 2006;Madhavan et al, 2009) and MSC , can significantly support endogenous neurogenesis during the degenerative process in animal models of PD (Hess and Borlongan, 2008). Neurogenesis has been confirmed in SVZ of human brains (Curtis et al, 2007), but its physiological role is still uncertain .…”