In vitro analysis of multipotent mesenchymal stromal cells as potential cellular therapeutics in neurometabolic diseases in pediatric patients
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In vitro analysis of multipotent mesenchymal stromal cells as potential cellular therapeutics in neurometabolic diseases in pediatric patients. / Müller, Ingo; Kustermann-Kuhn, Birgit; Holzwarth, Christina; Isensee, Gesa; Vaegler, Martin; Harzer, Klaus; Krägeloh-Mann, Ingeborg; Handgretinger, Rupert; Bruchelt, Gernot.
In: Experimental hematology, Vol. 34, No. 10, 10.2006, p. 1413-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - In vitro analysis of multipotent mesenchymal stromal cells as potential cellular therapeutics in neurometabolic diseases in pediatric patients
AU - Müller, Ingo
AU - Kustermann-Kuhn, Birgit
AU - Holzwarth, Christina
AU - Isensee, Gesa
AU - Vaegler, Martin
AU - Harzer, Klaus
AU - Krägeloh-Mann, Ingeborg
AU - Handgretinger, Rupert
AU - Bruchelt, Gernot
PY - 2006/10
Y1 - 2006/10
N2 - Multipotent mesenchymal stromal cells (MSCs) play an important role in stromal support for hematopoietic stem cells, immune modulation, and tissue regeneration. We investigated their potential as cellular therapeutic tools in neurometabolic diseases as a growing number of affected children undergo to bone marrow transplantation. MSCs were isolated from bone marrow aspirates and expanded ex vivo under various culture conditions. MSCs under optimal good medical practice (GMP)-conform culture conditions showed the typical morphology, immunophenotype, and plasticity. Biochemically, the activities of beta-hexosaminidase A, total beta-hexosaminidase, arylsulfatase A (ASA), and beta-galactosidase measured in MSCs were comparable to those in fibroblasts of healthy donors. These four enzymes were interesting for their expression in MSCs, as each of them is defective, respectively, in well-known neurometabolic diseases. We found that MSCs released significant amounts of ASA into the media. In coculture experiments, fibroblasts from patients with metachromatic leukodystrophy, who are deficient for ASA, took up a substantial amount of ASA that was released into the media from MSCs. Mannose-6-phosphate (M6P) inhibited this uptake, which was in accordance with the M6P receptor-mediated uptake of lysosomal enzymes. Taken together, we show that MSCs produce appreciable amounts of lysosomal enzyme activities, making these cells first-choice candidates for providing metabolic correction when given to enzyme-deficient patients. With the example of ASA, it was also shown that an enzyme secreted from MSCs is taken up by enzyme-deficient patient fibroblasts. Given the plasticity of MSCs, these cells represent an interesting add-on option for cellular therapy in children undergoing bone marrow transplantation for lysosomal storage diseases and other neurometabolic diseases.
AB - Multipotent mesenchymal stromal cells (MSCs) play an important role in stromal support for hematopoietic stem cells, immune modulation, and tissue regeneration. We investigated their potential as cellular therapeutic tools in neurometabolic diseases as a growing number of affected children undergo to bone marrow transplantation. MSCs were isolated from bone marrow aspirates and expanded ex vivo under various culture conditions. MSCs under optimal good medical practice (GMP)-conform culture conditions showed the typical morphology, immunophenotype, and plasticity. Biochemically, the activities of beta-hexosaminidase A, total beta-hexosaminidase, arylsulfatase A (ASA), and beta-galactosidase measured in MSCs were comparable to those in fibroblasts of healthy donors. These four enzymes were interesting for their expression in MSCs, as each of them is defective, respectively, in well-known neurometabolic diseases. We found that MSCs released significant amounts of ASA into the media. In coculture experiments, fibroblasts from patients with metachromatic leukodystrophy, who are deficient for ASA, took up a substantial amount of ASA that was released into the media from MSCs. Mannose-6-phosphate (M6P) inhibited this uptake, which was in accordance with the M6P receptor-mediated uptake of lysosomal enzymes. Taken together, we show that MSCs produce appreciable amounts of lysosomal enzyme activities, making these cells first-choice candidates for providing metabolic correction when given to enzyme-deficient patients. With the example of ASA, it was also shown that an enzyme secreted from MSCs is taken up by enzyme-deficient patient fibroblasts. Given the plasticity of MSCs, these cells represent an interesting add-on option for cellular therapy in children undergoing bone marrow transplantation for lysosomal storage diseases and other neurometabolic diseases.
KW - Bone Marrow Transplantation
KW - Cerebroside-Sulfatase
KW - Child
KW - Child, Preschool
KW - Coculture Techniques
KW - Female
KW - Fibroblasts
KW - Humans
KW - Leukodystrophy, Metachromatic
KW - Male
KW - Mesenchymal Stem Cell Transplantation
KW - Mesenchymal Stromal Cells
KW - Mucopolysaccharidosis I
KW - Multipotent Stem Cells
KW - Transplantation, Autologous
KW - Transplantation, Homologous
KW - beta-Galactosidase
KW - beta-N-Acetylhexosaminidases
U2 - 10.1016/j.exphem.2006.06.007
DO - 10.1016/j.exphem.2006.06.007
M3 - SCORING: Journal article
C2 - 16982334
VL - 34
SP - 1413
EP - 1419
JO - EXP HEMATOL
JF - EXP HEMATOL
SN - 0301-472X
IS - 10
ER -
