Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen


Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Mesenchymal Stem Cells

Adult stem cell populations isolated from various compartments in the mature organism can display an unexpected plasticity, a process previously thought to be an exclusive feature of ESCs. Subpopulations of adult stem cells are capable of differentiating into mature cells not related to their original lineage, a process termed 'transdifferentiation'. The most well-characterized adult stem cell population considered to possess a transdifferentiation capacity is bone marrow MSCs, also known as mesodermal stromal cells. Most studies on neuronal cell replacement involved the use of MSCs directly, while others differentiated them into neural cell population. In contrast to ESCs or NSCs, MSCs are easy to isolate, can be derived from the patient's own bone marrow and they represent a potential source for autologous cell transplantation, avoiding or reducing immunological rejections. MSCs usage for CRT circumvents the ethical problems concerning fetal tissue usage, thus making them attractive for regenerative medicine research. Despite initial skepticism regarding the capacity of MSCs to differentiate into neurons or glial cells, several studies have established the neurogenic predisposition of these cells as a result of the considerable repertoire of neural gene expression.[78–81] Undifferentiated MSCs transplanted into the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD improved mice motor functions and showed double-stained BrdU+/TH+ cells, indicating that the BrdU-labeled MSCs developed into DA cells in vivo.[82] Moreover, recent publications show that the differentiation process of neural-like cells induces the upregulation of genes involved in synaptic transmission, long-term potentialization[78] and the differentiated cells exhibit typical neuronal electrophysiological traits.[83–85] Rodent or human MSCs can be induced to differentiate into TH+ dopamine-producing cells that appear to be immature neuroblasts of DA lineage, which show weak electrical activity related to low expression levels of voltage-gated ion channels.[86,87] Functional maturity of these induced MSCs improves when the expression of the RE-1 (REST) silencing factor is knocked down by siRNA or by exposure to BDNF.[88,89] Differentiation of MSCs can be induced by exposure to soluble morphogenic proteins (FGFs and sonic hedgehog [SHH]),[39,90] chemical inducers (retinoic acid [RA], dibutyryl cyclic AMP [dbcAMP], 3-isobutyl-1-methylxanthine [IBMX], ascorbic acid [AA] and butylatedhydroxyanisole [BHA])[39,90] and also by lentiviral transduction of DA transcription factors (LMX1, NURR1 and PITX3).[86] Transplantation of induced human MSCs into the striatum of 6-OHDA hemiparkinsonian rats, ameliorated behavioral parameters, showing a reduction of 58–80% in apomorphine-induced rotations measured 85, 99 and 125 days after transplantation.[39]