Contamination of Mesenchymal Stem-Cells with Fibroblasts Accelerates Neurodegeneration in an Experimental Model of Parkinson’s Disease

Abstract

Pre-clinical studies have supported the use of mesenchymal stem cells (MSC) to treat highly prevalent neurodegenerative diseases such as Parkinson’s disease (PD) but preliminary trials have reported controversial results. In a rat model of PD induced by MPTP neurotoxin, we first observed a significant bilateral preservation of dopaminergic neurons in the substantia nigra and prevention of motor deficits typically observed in PD such as hypokinesia, catalepsy, and bradykinesia, following intracerebral administration of human umbilical cord-derived MSC (UC-MSC) early after MPTP injury. However, surprisingly, administration of fibroblasts, mesenchymal cells without stem cell properties, as a xenotransplantation control was highly detrimental, causing significant neurodegeneration and motor dysfunction independently of MPTP. This observation prompted us to further investigate the consequences of transplanting a MSC preparation contaminated with fibroblasts, a plausible circumstance in cell therapy since both cell types display similar immunophenotype and can be manipulated in vitro under the same conditions. Here we show for the first time, using the same experimental model and protocol, that transplantation of UC-MSC induced potent neuroprotection in the brain resulting in clinical benefit. However, co-transplantation of UC-MSC with fibroblasts reverted therapeutic efficacy and caused opposite damaging effects, significantly exacerbating neurodegeneration and motor deficits in MPTP-exposed rats. Besides providing a rationale for testing UC-MSC transplantation in early phases of PD aiming at delaying disease progression, our pre-clinical study suggests that fibroblasts may be common cell contaminants affecting purity of MSC preparations and clinical outcome in stem cell therapy protocols, which might also explain discrepant clinical results.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-011-9256-4) contains supplementary material, which is available to authorized users.

Do mesenchymal stem cells function across species barriers? Relevance for xenotransplantation

“…Liu et al [40] demonstrated that human bone marrow-derived MSC may accelerate human breast tumor growth in NOD/SCID mice by generating cytokines that affect the cancer stem cell population. Pereira et al [41] reported that co-transplantation of human umbilical cord-derived MSC with fibroblasts exacerbated neurodegeneration in a rat model of Parkinson's disease.…”

Comparison between fibroblasts and mesenchymal stem cells derived from dermal and adipose tissue

“…The author also pointed out that fibroblasts share a therapeutic potential with MSC [39]. Other authors and studies, however, have demonstrated that the contamination with fibroblasts can be one of the reasons why promising cell therapies are failing in the pre-clinical testing stages [8].…”

A Meta-Analysis of Mesenchymal Stem Cells in Animal Models of Parkinson's Disease

“…There were 20 experiments conducted to evaluate rotational behavior and 8 experiments conducted to evaluate limb function. In addition, there were three studies using the rotarod test [36,81,83] and three studies using the open field test [80,84,89]. Because of insufficient numbers, these studies on rotarod and open field were not included in the meta-analysis.…”