Lmx1a enhances the effect of iNSCs in a PD model

Abstract

Lmx1a plays a central role in the specification of dopaminergic (DA) neurons, which potentially could be employed as a key factor for trans-differentiation to DA neurons. In our previous study, we have converted somatic cells directly into neural stem cell-like cells, namely induced neural stem cells (iNSCs), which further can be differentiated into subtypes of neurons and glia in vitro. In the present study, we continued to test whether these iNSCs have therapeutic effects when transplanted into a mouse model of Parkinson's disease (PD), especially when Lmx1a was introduced into these iNSCs under a Nestin enhancer. iNSCs that over-expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro. When transplanted into mouse models of PD, both groups of mice showed decreased ipsilateral rotations; yet mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery. Although few iNSCs survived 11weeks after transplantation, the improved motor performance in iNSC-Lmx1a group did correlate with a greater tyrosine hydroxylase (TH) signal abundance in the lesioned area of striatum, suggesting that iNSCs may have worked through a non-autonomous manner to enhance the functions of remaining endogenous dopaminergic neurons in brain.

Development of stem cell-based therapies for Parkinson's disease

“…Brn4 and tyrosine hydroxylase (TH) synergistically promote the differentiation of neural stem cells into dopaminergic neurons and increase cell survival and DA release of dopaminergic neurons [20,21]. Recently, it has been found that induced neural stem cells (iNSCs) that over-expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro and mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery [22]. However, major hurdles in relation to the use of NSCs for the generation of DA neurons need to be overcome before they can be clinically applied for the treatment of PD.…”

Generation of diverse neural cell types through direct conversion

“…In addition to cellular replacement, transplanted induced cells were shown to exert their therapeutic effect through neuroprotective and immunomodulatory mechanisms, as well as promotion of endogenous regeneration, as evident by decreased expression of apoptotic and inflam matory markers [151] . Similarly, mouse Sertoli cell-derived induced neural stem cells exogenously expressing the dopaminergic neuron-specific factor Lmx1a were transplanted into the striatum of Parkinson's disease model mice [152] . While transplantation of induced neural stem cells was shown to improve the motor performance of mouse models, with greater tyrosine hydroxylase signal abundance in the lesioned area, only few transplanted cells survived over time, thus suggesting that the therapeutic effects may have occurred in a nonautonomous manner through enhancement of the functions of remaining endogenous cells [152] .…”

“…Similarly, mouse Sertoli cell-derived induced neural stem cells exogenously expressing the dopaminergic neuron-specific factor Lmx1a were transplanted into the striatum of Parkinson's disease model mice [152] . While transplantation of induced neural stem cells was shown to improve the motor performance of mouse models, with greater tyrosine hydroxylase signal abundance in the lesioned area, only few transplanted cells survived over time, thus suggesting that the therapeutic effects may have occurred in a nonautonomous manner through enhancement of the functions of remaining endogenous cells [152] . Interestingly, induced neural cell types generated via direct conversion with lineagespecific factors have been shown to possess greater chromosomal stability than neural cells derived from pluripotent or adult stem cells [124] , further promoting the clinical potential of neural cell types generated via direct conversion.…”

Cell Therapy for Parkinson’s Disease: New Hope from Reprogramming Technologies

“…These iNSCs can self-renew and differentiate to different neuronal subtypes including DA neurons. Importantly, they can also survive transplantation and differentiate to neurons after being introduced into the dentate gyrus of adult hippocampus [49] or naïve and 6-OHDA-lesioned striatum of mice [50]. Other groups have also reported iNSCs converted from mouse and human somatic cells [51,52].…”