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• W1998667654 abstract "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 β-hexosaminidase A, total β-hexosaminidase, arylsulfatase A (ASA), and β-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. 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 β-hexosaminidase A, total β-hexosaminidase, arylsulfatase A (ASA), and β-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. Friedenstein et al. and, in more detail, Caplan described mesenchymal stem cells decades ago [1Friedenstein A.J. Chailakhyan R.K. Latsinik N.V. Panasyuk A.F. Keiliss-Borok I.V. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo.Transplantation. 1974; 17: 331-340Crossref PubMed Scopus (1071) Google Scholar, 2Caplan A.I. Mesenchymal stem cells.J Orthop Res. 1991; 9: 641-650Crossref PubMed Scopus (3340) Google Scholar]. Recently these cells have been termed more precisely “multipotent mesenchymal stromal cells” (MSCs) [3Horwitz E.M. Le B.K. Dominici M. et al.Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement.Cytotherapy. 2005; 7: 393-395Abstract Full Text Full Text PDF PubMed Scopus (1449) Google Scholar]. MSCs have earned considerable clinical attention in regenerative and transplantation medicine due to their plasticity and immunomodulatory properties [4Krampera M. Glennie S. Dyson J. et al.Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood. 2003; 101: 3722-3729Crossref PubMed Scopus (1358) Google Scholar]. The supportive function of MSCs for hematopoietic stem cells (HSCs), which was shown in numerous in vitro experiments, also seemed to relate to clinical findings, when patients with mamma carcinoma who received high-dose chemotherapy were rescued with both autologous HSCs and MSCs [5Noort W.A. Kruisselbrink A.B. in't Anker P.S. et al.Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice.Exp Hematol. 2002; 30: 870-878Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 6Koc O.N. Gerson S.L. Cooper B.W. et al.Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy.J Clin Oncol. 2000; 18: 307-316PubMed Google Scholar]. As bone marrow stroma suffers extensive damage during high-dose chemotherapy in myeloablative regimens, this function of MSCs is potentially beneficial to reduce the aplastic period [7Galotto M. Berisso G. Delfino L. et al.Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients.Exp Hematol. 1999; 27: 1460-1466Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar]. However, MSCs are not transplanted successfully in current protocols for bone marrow transplantation (BMT) or peripheral blood stem cell transplantation and remain host-derived in almost all cases with careful analysis [8Rieger K. Marinets O. Fietz T. et al.Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation.Exp Hematol. 2005; 33: 605-611Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 9Wang J. Liu K. Lu D.P. Mesenchymal stem cells in stem cell transplant recipients are damaged and remain of host origin.Int J Hematol. 2005; 82: 152-158Crossref PubMed Scopus (20) Google Scholar]. MSCs have been applied in children with metachromatic leukodystrophy (MLD) or Hurler syndrome (MPS-IH) months or years after they had undergone allogeneic BMT [10Koc O.N. Day J. Nieder M. et al.Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).Bone Marrow Transplant. 2002; 30: 215-222Crossref PubMed Scopus (573) Google Scholar]. Some of these children improved and successful engraftment of MSCs in the bone marrow was shown in two patients. These initial results show that patients might have a benefit from application of MSCs when culture conditions and transplantation protocols are optimized. In our previous work we have developed a culture system that allows for good medical practice (GMP)-conform expansion of MSCs ex vivo (Müller et al., in press). Moreover, immunogenic animal serum constituents have been eliminated, possibly promoting engraftment of MSCs in immune-competent recipients. These patients frequently developed antibodies against bovine serum albumin, for example, which has been a culture constituent in almost all trials conducted to date [11Horwitz E.M. Gordon P.L. Koo W.K. et al.Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone.Proc Natl Acad Sci U S A. 2002; 99: 8932-8937Crossref PubMed Scopus (1386) Google Scholar]. The rationale for application of MSCs in neurometabolic disorders is appealing, as these cells have been shown to distribute throughout the body and to contribute to a wide variety of tissues [12Almeida-Porada G. Zanjani E.D. A large animal noninjury model for study of human stem cell plasticity.Blood Cells Mol Dis. 2004; 32: 77-81Crossref PubMed Scopus (25) Google Scholar]. As in most lysosomal storage disorders the central nervous system (CNS) is predominantly affected, and migration of MSCs into the CNS is a critical issue. In several in vivo models it was shown that MSCs reached the brain after intravenous or intraperitoneal transfusion [13McBride C. Gaupp D. Phinney D.G. Quantifying levels of transplanted murine and human mesenchymal stem cells in vivo by real-time PCR.Cytotherapy. 2003; 5: 7-18Abstract Full Text PDF PubMed Scopus (97) Google Scholar]. In addition, the homing process of MSCs is further promoted by trauma or other damage leading to an inflammatory reaction [14Wang L. Li Y. Chen J. et al.Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture.Exp Hematol. 2002; 30: 831-836Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 15Francois S. Bensidhoum M. Mouiseddine M. et al.Local irradiation induces not only homing of human mesenchymal stem cells (hMSC) at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution following irradiation damages.Stem Cells. 2006; 24: 1020-1029Crossref PubMed Scopus (317) Google Scholar]. Some neurometabolic disorders are known to be accompanied by inflammatory reactions in the CNS and recruitment of MSCs to affected sites has been hypothesized. However, the local effect of MSCs in the CNS is not well understood. The immunomodulatory effects of MSCs in vitro and in vivo enable these cells to inhibit inflammatory processes, thus preventing further destruction of neurons. Nevertheless, the question of how an inborn error of metabolism in terminally differentiated cells might be corrected by BMT is a conceptual challenge. In the present study we investigated the properties of MSCs that are considered most valuable when administering these cells to patients with neurometabolic diseases such as MLD and others: 1) immune modulation; 2) plasticity (e.g., in osseous affections); and finally 3) activities of lysosomal enzymes in MSCs and possible transmission of these enzymes to enzyme-deficient patient cells. Here, we show that MSCs raised under animal serum-free conditions can exert immunomodulatory functions on various subsets of lymphocytes. Moreover, differentiation into osteoblasts can be achieved under these conditions. Most importantly, MSCs produce ample activities of lysosomal enzymes. In addition, MSCs release arylsulfatase A (ASA) into the culture media and enzyme-deficient fibroblasts from MLD patients take up this protein and achieve significant activities in this model of metabolic correction. Patient material was obtained after informed consent of the parents and approved by the local Institutional Review Board of the University hospital Tübingen, Germany. Excessive material obtained from diagnostic bone marrow aspirates of children with hematopoietic malignancies was heparinized and subjected to red blood cell lysis using the ammonium chloride method. Subsequently, cells were washed in phosphate-buffered saline (PBS) and placed in Dulbecco's Modified Eagle Medium (DMEM) medium containing 10% (v/v) fetal calf serum (FCS), 1 mM glutamine, 100 I.E./mL penicillin, and 100 μg/mL streptomycin. Cells from 1 mL bone marrow were placed in one well of a six-well culture plate. Nonadherent cells were purged on day 2 and medium was replaced once a week or more often when necessary. Coculture of MSCs and fibroblasts were performed in transwell system using the six-well plate format (Costar, Bodenheim, Germany), where MSCs were kept on a membrane, allowing for molecule exchange but not cell migration, and the fibroblasts were grown on the plate in the lower chamber. Enzymatic assays were performed from medium as well as from cell homogenates after two freeze-thaw cycles [4Krampera M. Glennie S. Dyson J. et al.Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood. 2003; 101: 3722-3729Crossref PubMed Scopus (1358) Google Scholar]. Supernatant (50 μL) of lysed MSCs (at 6 × 105 cells/mL) were incubated with 200 μL substrate solution (10 mM p-nitrocatecholsulfate/0.5 mM sodium pyrophosphate/10% sodium chloride in 0.5 M sodium acetate buffer; pH 5.0) for 48 hours at 8°C. Thereafter, the reaction was stopped with 250 μL 0.5 M NaOH and measured photometrically at 514 nm against water. Sample blank was incubated in the same way, except that 250 μL 0.5 M NaOH was added already at t = 0. Cell homogenate (30 μL; 6× 105 cells/mL) were incubated with 75 μL substrate solution (800 μg p-nitophenyl-6-sulpho-2-acetamido-2-deoxy-D glucopyranoside/1 mL H2O ddH2O) + 225 μL buffer (0.1 M citric acid, adjusted to pH 4.0 with 0.2 M disodium hydrogen phosphate solution) for 100 minutes at 37°C. The reaction was stopped with 250 μL 0.5 M NaOH and measured photometrically against H2O at 405 nm. Sample blank: 30 μL cell homogenate + 225 μL buffer + 250 μL 0.5 M NaOH were incubated for 100 minutes; 75 μL substrate solution were incubated separately under the same conditions. Both solutions were combined before reading. Cell homogenate (30 μL; 6× 105 cells/mL) were added to 250 μL substrate solution (7 mg p-nitrophenyl-N-acetyl-ß-D-glucosaminidine in 10 mL citrate buffer; pH 4.5). After addition of 50 μL citrate buffer (0.1 M; pH 4.5), the reaction mixture was incubated for 45 minutes at 37°C. Thereafter, the incubation was stopped with 250 μL 0.5 M NaOH and measured photometrically at 405 nm. Blank: 30 μL cell homogenate, 50 μL citrate buffer, and 250 μL 0.5 M NaOH, and, separately, 250 μL substrate solution were incubated for 45 minutes. Both solutions were combined before reading at 405 nm. Cell homogenate (40 μL; 6 × 105 cells/mL) + 150 μL substrate solution (6 mg p-nitrophenyl-ß-D-galactopyranoside/10 mL sodium acetate buffer 1 [0.25 M Na-acetate/0.5 M NaCl, adjusted with acetic acid to pH 4.5]) and 100 μL sodium acetate buffer 2 (0.25 M sodium acetate, adjusted with acetic acid to pH 4.5) were incubated for 2 hours at 37°C. The reaction was stopped with 250 μL 0.5 M NaOH and absorption was measured at 405 nm. Blank: 40 μL cell lysate, 100 μL buffer, and 250 μL 0.5 M NaOH and, separately, 150 μL substrate solution were incubated at 37°C for 2 hours. Before reading at 405 nm, both samples were combined. Flow cytometric analysis was performed on a FACS Calibur (Becton Dickinson, Heidelberg, Germany) and data were analyzed by the CellQuest software (Becton Dickinson). Anti-CD4-phycoerythrin (PE) (RPA-T4), anti-CD8-PE (SK 1), anti-immunoglobulin 1 (IgG1)-fluorescein isothiocyanate (FITC) (clone MOPC-31C), anti-IgG1-PE (clone G18-145), anti-CD45-FITC (HI30), anti-CD34-PE (563), anti-CD73-PE (A02), anti-HLA-DR-FITC (TÜ36), and anti-HLA-ABC-PE (G46-2.6) antibodies were obtained from Becton Dickinson; in addition the following antibodies were used: anti-CD105-FITC (N1-3A1, Ancell, Bayport, MN, USA), anti-CD90-PE (F15-42-1), anti-CD106 (1.G11B1, both Serotec, Düsseldorf, Germany), anti-CD146-PE (P1H12, Santa Cruz Biotechnology, Heidelberg, Germany). MSCs were induced toward the osteogenic lineage. MSCs were seeded in bone induction medium with low glucose-DMEM (Gibco) containing 10% FCS (Hyclone, Logan, UT, USA), 104 IU/mL penicillin, 10 mg/mL streptomycin, glutamine (2 mM), supplemented with dexamethasone (10 nM), L-ascorbic acid-2-phosphate (0.1 mM), beta-glycerol phosphate (10 mM) (all Sigma, Munich, Germany), and bone morphogenic protein-2 (100 ng/mL) (Tebu-Bio, Magenta, Italy). After 2 weeks, differentiated MSCs and controls were stained with aqueous 0.5% (v/v) Alizarin Red-S (Sigma) and washed with PBS. Carboxy-fluorescein diacetate succinimidyl ester (CFSE) diffuses freely into cells and intracellular esterases cleave the acetate groups, converting it to a fluorescent, membrane impermeant dye. During each round of cell division, the relative intensity of the dye is decreased by half. Peripheral blood mononuclear cells (PBMCs) from healthy volunteer donors were CFSE-labeled according to the manufacturer's protocol (Roche, Mannheim, Germany). HLA-mismatched PBMCs (50,000) were added per well of a 96-well plate (Greiner, Frickenhausen, Germany) already containing 20,000 MSCs where indicated. Phytohemagglutinin (PHA, 5 μM; Sigma), was used as mitogen in these cultures where indicated. PBMCs were analyzed by flow cytometry after 5 days as outlined above. MSCs were isolated from 0.5 mL aspirates of heparinized bone marrow. MSC cultures were established in DMEM supplemented with platelet-rich plasma or with FCS, respectively. These MSCs were morphologically indistinguishable from MSCs cultivated in FCS-supplemented media (triangular at low-density seeding and spindle-shaped at confluency, Fig. 1A and B). Cell surface expression of characteristic markers was analyzed by flow cytometry. MSCs expanded under the conditions detailed above proved to have the characteristic phenotype with expression of CD73, CD105, CD106, CD90, CD146, HLA-ABC and the lack of CD34, CD45, and HLA-DR (Fig. 1C and D). After 4 weeks of culture, these MSC populations displayed a purity of more than 95% as shown by CD73/CD105 coexpression. Several lysosomal storage diseases and other neurometabolic disorders affect bone metabolism resulting in dysmorphic and brittled bones. Therefore, therapeutic efforts target bone metabolism and MSCs, which are known to differentiate into osteoblasts under appropriate conditions. Consequently, MSCs grown under animal serum-free conditions for enzymatic assays were analyzed for their ability to differentiate into osteoblasts. Figure 2 proves that MSCs can be differentiated into osteoblasts as indicated by deposition of phosphate salts in the Alizarin red staining. In addition, MSCs might have a beneficial effect on the accompanying inflammatory processes in neurometabolic diseases. Therefore, we confirmed that the MSCs used for the enzymatic assays show the immunomodulatory effect in mitogen-induced proliferation of PBMCs (Fig. 2C, D). When considering to include MSCs into cellular treatment strategies of lysosomal storage disorders, it is essential to prove sufficient activity of relevant enzymes in these cells. We focused on four enzymes in the present study: ASA, β−hexosaminidase A, total β-hexosaminidase and β-galactosidase (deficient in metachromatic leukodystrophy, Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis, respectively). For all four enzymes, the mean activity levels in MSCs were shown to be similar to those in normal fibroblasts (Fig. 3). As expected for lysosomal enzymes, these activities were not confined to the intracellular compartments of MSCs. ASA has been shown to be secreted in particular after genetic or enzymatic modification in humans and in donor cells used for a corresponding mouse model of MLD [16Matzner U. Schestag F. Hartmann D. et al.Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells.Hum Gene Ther. 2001; 12: 1021-1033Crossref PubMed Scopus (35) Google Scholar, 17Muschol N. Matzner U. Tiede S. et al.Secretion of phosphomannosyl-deficient arylsulphatase A and cathepsin D from isolated human macrophages.Biochem J. 2002; 368: 845-853Crossref PubMed Scopus (25) Google Scholar]. These findings led us to analyze whether MSCs release wild-type ASA into the culture media. Figure 4 shows that there is, indeed, an accumulation of ASA activity in the culture medium of MSCs. Obviously, it would be beneficial for ASA-deficient MLD cells to take up the enzyme from the media, thereby compensating their endogenous enzyme deficiency. This concept is the basis of all enzyme replacement strategies using repetitive infusions of recombinant enzyme. In our setting, MLD fibroblasts, spatially separated from healthy MSCs by a semipermeable membrane in a transwell experiment, readily took up ASA released from MSCs into the media (Fig. 4). Mannose-6-phosphate inhibited the intracellular accumulation of ASA in MLD fibroblasts, suggesting that this process was dependent on the mannose-6-phosphate receptor, as shown in Figure 5.Figure 5The uptake of ASA from the culture supernatant of healthy MSCs by ASA-deficient fibroblasts of a patient with MLD is inhibited by 5 mM mannose-6-phosphate (M6P). ASA activity was measured after 6 days by photometry of the artificial reaction product at 514 nm.View Large Image Figure ViewerDownload (PPT) Taken together, these experiments showed that MSCs are interesting tools in cellular enzyme replacement strategies involving allogeneic BMT and stem cell transplantation. The use of MSCs in BMT has been suggested not only because of the supportive function of MSCs for HSCs but also because of their plasticity and immunomodulatory effects. We have performed 13 applications of MSCs after culture expansion in pediatric patients to date (Müller et al., submitted). There were no adverse effects associated with the transfusion. This observation is encouraging and may further stimulate applications of MSCs in pediatric diseases such as lysosomal storage diseases [18Koc O.N. Peters C. Aubourg P. et al.Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.Exp Hematol. 1999; 27: 1675-1681Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. We have optimized the procedure for expansion and administration of MSCs to allow for successful engraftment of MSCs. Although for modulation of immune responses a permanent engraftment of MSCs may not be essential, for sustained function in neurometabolic disorders a long-term engraftment of MSCs is indispensable. Successful long-term engraftment of MSCs has already been achieved in children with other inborn errors of metabolism [19Le Blanc K. Gotherstrom C. Ringden O. et al.Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta.Transplantation. 2005; 79: 1607-1614Crossref PubMed Scopus (374) Google Scholar]. The first successful clinical application was performed in children with osteogenesis imperfecta, who received MSCs and experienced a clinical benefit in several disease parameters. Further clinically relevant investigations including cardiac remodeling after infarction show that MSCs increased myocardial contractility and reduced contralateral wall thickening [20Kawada H. Fujita J. Kinjo K. et al.Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction.Blood. 2004; 104: 3581-3587Crossref PubMed Scopus (520) Google Scholar]. Regenerative properties of MSCs were also documented in spinal cord injury, where locally implanted MSCs migrated toward the lesion and differentiated into nestin-positive cells [21Satake K. Lou J. Lenke L.G. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue.Spine. 2004; 29: 1971-1979Crossref PubMed Scopus (134) Google Scholar]. Obviously, MSCs are very attractive tools in cellular therapy of degenerative diseases. However, any adult stem cell cannot replace cells of terminally differentiated organs and any therapeutic strategy should aim at the support of existing cells including delivery of sufficient amounts of active enzyme to restore normal cellular functions in the case of enzymopathies. This approach has been taken by enzyme replacement therapy using recombinant proteins in some entities [22Brady R.O. Schiffmann R. Enzyme-replacement therapy for metabolic storage disorders.Lancet Neurol. 2004; 3: 752-756Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. These enzymes poorly penetrate the blood-brain barrier and often do not improve bone lesions [23Lebel E. Dweck A. Foldes A.J. et al.Bone density changes with enzyme therapy for Gaucher disease.J Bone Miner Metab. 2004; 22: 597-601Crossref PubMed Scopus (41) Google Scholar, 24Miebach E. Enzyme replacement therapy in mucopolysaccharidosis type I.Acta Paediatr Suppl. 2005; 94: 58-60Crossref PubMed Scopus (40) Google Scholar]. It is therefore desirable to establish a continuous local source of the respective enzyme in compartments, which are difficult to reach either because of anatomic structures or because they are bradytrophic tissues. We have shown that MSCs grown under our animal serum-free conditions are able to differentiate into osteoblasts, and they have been employed in inborn errors of bone metabolism already. In addition, MSCs have proven their homing and regenerative potential in various models of neuronal and brain damage [25Sakurai K. Iizuka S. Shen J.S. et al.Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice.Gene Ther. 2004; 11: 1475-1481Crossref PubMed Scopus (32) Google Scholar, 26Satake K. Lou J. Lenke L.G. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue.Spine. 2004; 29: 1971-1979Crossref PubMed Scopus (193) Google Scholar, 27Thalmeier K. Meissner P. Moosmann S. et al.Mesenchymal differentiation and organ distribution of established human stromal cell lines in NOD/SCID mice.Acta Haematol. 2001; 105: 159-165Crossref PubMed Scopus (31) Google Scholar]. Hence, MSCs are characterized by several features, which make them an important tool in cellular therapies of neurometabolic diseases. There are initial experiments that have used MSCs as gene shuttle and thus may facilitate the development of gene therapy approaches in autologous transplantation settings [28Gieselmann V. Matzner U. Klein D. et al.Gene therapy: prospects for glycolipid storage diseases.Philos Trans R Soc Lond B Biol Sci. 2003; 358: 921-925Crossref PubMed Scopus (19) Google Scholar]. Although the correction of the gene defect appeals to the idea of a causal treatment, safety issues have to be considered in the light of recent complications in treatment of children with immune deficiency by gene therapy [29Hacein-Bey-Abina S. Von K.C. Schmidt M. et al.LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.Science. 2003; 302: 415-419Crossref PubMed Scopus (2909) Google Scholar]. Until further improvement of this technique, allogeneic stem cell transplantation provides an alternative, which has become a safe procedure with rates of transplant related mortality below 3% in centers with extensive experience [30Grigull L. Beilken A. Schrappe M. et al.Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler).Bone Marrow Transplant. 2005; 35: 265-269Crossref PubMed Scopus (29) Google Scholar, 31Lang P. Schumm M. Greil J. et al.A comparison between three graft manipulation methods for haploidentical stem cell transplantation in pediatric patients: preliminary results of a pilot study.Klin Padiatr. 2005; 217: 334-338Crossref PubMed Scopus (70) Google Scholar]. The strategy of allogeneic stem cell transplantation might help to restore enzyme activities in all compartments and to prevent progression of the disease or even lead to some clinical improvements. There are first reports describing some encouraging results for MLD, MPS-IH, and other diseases [32Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases.Springer Semin Immunopathol. 2004; 26: 119-132Crossref PubMed Scopus (147) Google Scholar]. However, it is known that the conditioning regimen and transplant maneuver used in these children do not lead to a successful engraftment of donor MSCs in the recipient [9Wang J. Liu K. Lu D.P. Mesenchymal stem cells in stem cell transplant recipients are damaged and remain of host origin.Int J Hematol. 2005; 82: 152-158Crossref PubMed Scopus (20) Google Scholar, 18Koc O.N. Peters C. Aubourg P. et al.Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.Exp Hematol. 1999; 27: 1675-1681Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. On the other hand, the transplantation of ex vivo expanded MSCs and successful engraftment in these patients has been shown by Koc and colleagues [10Koc O.N. Day J. Nieder M. et al.Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).Bone Marrow Transplant. 2002; 30: 215-222Crossref PubMed Scopus (573) Google Scholar]. Taken together, the clinical experience with allogeneic stem cell transplantation in combination with the present analyses of enzyme activities in MSCs and exchange of enzyme with other cell types strongly argue for a transplantation procedure including expanded MSCs early in the course of eligible enzyme-deficiency diseases. This work was supported by the fortune program of the UKT Tübingen and by the Förderverein für krebskranke Kinder Tübingen e. V. I.M. is a recipient of the Kind-Philipp-Rückkerstipendium of the Bauer-Stiftung zur Förderung von Wissenschaft und Bildung." @default.
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• W1998667654 title "In vitro analysis of multipotent mesenchymal stromal cells as potential cellular therapeutics in neurometabolic diseases in pediatric patients" @default.
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• W1998667654 doi "https://doi.org/10.1016/j.exphem.2006.06.007" @default.
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