Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells.
Mucopolysaccharidoses (MPS) are inherited metabolic disorders that arise from a complete loss or a reduction in one of eleven specific lysosomal enzymes. MPS children display pathology in multiple cell types leading to tissue and organ failure and early death. Mesenchymal stem cells (MSCs) give rise to many of the cell types affected in MPS, including those that are refractory to current treatment protocols such as hematopoietic stem cell (HSC) based therapy. In this study we compared multiple MPS enzyme production by bone marrow derived (hBM) and dental pulp derived (hDP) MSCs to enzyme production by HSCs. hBM MSCs produce significantly higher levels of MPS I, II, IIIA, IVA, VI and VII enzyme than HSCs, while hDP MSCs produce significantly higher levels of MPS I, IIIA, IVA, VI and VII enzymes. Higher transfection efficiency was observed in MSCs (89%) compared to HSCs (23%) using a lentiviral vector. Over-expression of four different lysosomal enzymes resulted in up to 9303-fold and up to 5559-fold greater levels in MSC cell layer and media respectively. Stable, persistent transduction of MSCs and sustained over-expression of MPS VII enzyme was observed in vitro. Transduction of MSCs did not affect the ability of the cells to differentiate down osteogenic, adipogenic or chondrogenic lineages, but did partially delay differentiation down the non-mesodermal neurogenic lineage.
Genetics and Molecular Pathology, SA Pathology, North Adelaide, South Australia, Australia; Department of Genetics, The University of Adelaide, South Australia, Australia.
Matilda
M
Jackson
Genetics and Molecular Pathology, SA Pathology, North Adelaide, South Australia, Australia; Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia.
Ainslie
A
Derrick Roberts
Department of Genetics, The University of Adelaide, South Australia, Australia.
Ellenore
E
Martin
Genetics and Molecular Pathology, SA Pathology, North Adelaide, South Australia, Australia; Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia.
Nathan
N
Rout-Pitt
Mesenchymal Stem Cell Laboratory, School of Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
Stan
S
Gronthos
Genetics and Molecular Pathology, SA Pathology, North Adelaide, South Australia, Australia; Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia; Department of Genetics, The University of Adelaide, South Australia, Australia. Electronic address: sharon.byers@adelaide.edu.au.
Sharon
S
Byers
D001853:Bone Marrow; D002454:Cell Differentiation; D002478:Cells, Cultured; D003782:Dental Pulp; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D009083:Mucopolysaccharidoses / Q000201:enzymology*; D016538:Mucopolysaccharidosis VII / Q000235:genetics; D014161:Transduction, Genetic
D006025:Glycosaminoglycans; D005966:Glucuronidase
Differentiation; Glycosaminoglycan; Hematopoietic stem cells; Mesenchymal stem cell; Mucopolysaccharidosis