title: 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.
authors.affiliation: Disciplina de Neurologia Experimental, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Marcia C L
authors.initials: MC
authors.lastname: Pereira
authors.forename: Mariane
authors.initials: M
authors.lastname: Secco
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Suzuki
authors.forename: Luciana
authors.initials: L
authors.lastname: Janjoppi
authors.forename: Carolina O
authors.initials: CO
authors.lastname: Rodini
authors.forename: Layla B
authors.initials: LB
authors.lastname: Torres
authors.forename: Bruno H S
authors.initials: BH
authors.lastname: Araújo
authors.forename: Esper A
authors.initials: EA
authors.lastname: Cavalheiro
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Oswaldo Keith
authors.initials: OK
authors.lastname: Okamoto
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D023421:Models, Animal; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000473:pathology* / Q000628:therapy; D051381:Rats; D017208:Rats, Wistar; D014183:Transplantation, Heterologous; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine