Glial cell line‐derived neurotrophic factor–secreting genetically modified human bone marrow‐derived mesenchymal stem cells promote recovery in a rat model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal dopaminergic (DA) neurons. The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF), the most potent neurotrophic factor for DA neurons, has been demonstrated in many experimental models of PD. However, chronic delivery of GDNF to DA neurons in the brain remains an unmet challenge. Here, we report the effects of GDNF-releasing Notch-induced human bone marrow-derived mesenchymal stem cells (MSC) grafted into striatum of the 6-hydroxydopamine (6-OHDA) progressively lesioned rat model of PD. Human MSC, obtained from bone marrow aspirates of young, healthy adult volunteers, were transiently transfected with the intracellular domain of the Notch1 gene (NICD) to generate SB623 cells. SB623 cells expressing GDNF and/or humanized Renilla green fluorescent protein (hrGFP) following lentiviral transduction or nontransduced cells were stereotaxically placed into rat striatum 1 week after a unilateral partial 6-OHDA striatal lesion. At 4 weeks, rats that had received GDNF-transduced SB623 cells had significantly decreased amphetamine-induced rotation compared with control rats, although this effect was not observed in rats that received GFP-transduced or nontransduced SB623 cells. At 5 weeks, rejuvenated tyrosine hydroxylase-immunoreactive (TH-IR) fibers that appeared to be host DA axons were observed in and around grafts. This effect was more prominent in rats that received GDNF-secreting cells and was not observed in controls. These observations suggest that human bone-marrow derived MSC, genetically modified to secrete GDNF, hold potential as an allogeneic or autologous stem cell therapy for PD.

Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats

“…It was previously reported that naïve, neurotrophic factorsecreting, or neurally induced MSCs have therapeutic effects when transplanted into 6-OHDA-or MPTP-induced Parkinsonian animals (Biju et al, 2013;Capitelli et al, 2014;Dezawa et al, 2004;Glavaski-Joksimovic et al, 2010;McCoy et al, 2008;Park et al, 2014;Sadan et al, 2009;Wang et al, 2013;Weiss et al, 2006;Yan et al, 2013). A beneficial effect of the striatal transplantation of both SHEDs and DAergic neuronlike SHEDs was also previously reported (Wang et al, 2010).…”

Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine

“…Studies carried out with PD rat models show some examples of the substantial, beneficial behavioural results after engineered BM-MSC administration with either GDNF [216,217] or persephin [218], which is another neurotrophic factor that promotes survival, proliferation, and differentiation of neurons [219]. demyelination and neuronal loss [220].…”

“…ecSOD [158] GLP-1 [160] HCN1 [19] HCN4 [186,187] Fn14 [189] Wnt11 [164] HO-1 [167,168] My GA NEURAL DIFFERENTIATION AND REPAIR BDNF [22] [201] [203,204] GDNF [20] [207] [216,217] NGF [236] NT-3 [225,226] MNTS-1 [230] Shh [232] VEGF [21] GLP-1 [215] VIP [221] IL-10 [222] interferon-β [223] CXCR4 [205] TrkC [228] Ng Ng RA Nu Ma KIDNEY REPAIR HGF [23] GSTM1 [267] Survivin [268] …”

An Update on Gene Therapy in Parkinson’s Disease

“…In rodent models of PD, continuous levodopa delivery by transferring genes for TH and GCH1 via an rAAV vector to striatal neurons has prevented dyskinesia and reversed both dyskinesia and sensorimotor behavioral deficits [81,82]. GDNF continues to be investigated via several different gene delivery techniques, including lentiviral vector and stem cells transduced ex vivo with the GDNF gene [83,84].…”