title: Systemic delivery of bone marrow-derived mesenchymal stromal cells diminishes neuropathology in a mouse model of Krabbe's disease.
abstract: In Krabbe's disease, a demyelinating disorder, add-on strategies targeting the peripheral nervous system (PNS) are needed, as it is not corrected by bone-marrow (BM) transplantation. To circumvent this limitation of BM transplantation, we assessed whether i.v. delivery of immortalized EGFP(+) BM-derived murine mesenchymal stromal cells (BM-MSC(TERT-EGFP) ) targets the PNS of a Krabbe's disease model, the Twitcher mouse. In vitro, BM-MSC(TERT-EGFP) retained the phenotype of primary BM-MSC and did not originate tumors upon transplantation in nude mice. In vivo, undifferentiated EGFP(+) cells grafted the Twitcher sciatic nerve where an increase in Schwann cell precursors and axonal number was detected. The same effect was observed on BM-MSC(TERT-EGFP) i.v. delivery following sciatic nerve crush, a model of axonal regeneration. Reiterating the in vivo findings, in a coculture system, BM-MSC(TERT-EGFP) induced the proliferation of Twitcher-derived Schwann cells and the neurite outgrowth of both Twitcher-derived neurons and wild-type neurons grown in the presence of psychosine, the toxic substrate that accumulates in Krabbe's disease. In vitro, this neuritogenic effect was blocked by K252a, an antagonist of Trk receptors, and by antibody blockage of brain derived neurotrophic factor, a neurotrophin secreted by BM-MSC(TERT-EGFP) and induced in neighboring Schwann cells. In vivo, BM-MSC(TERT-EGFP) surmounted the effect of K252a, indicating their ability to act through a neurotrophin-independent mechanism. In summary, i.v. delivery of BM-MSC(TERT-EGFP) exerts a multilevel effect targeting neurons and Schwann cells, coordinately diminishing neuropathology. Therefore, to specifically target the PNS, MSC should be considered an add-on option to BM transplantation in Krabbe's disease and in other disorders where peripheral axonal loss occurs.
authors: Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal.
authors: Catarina Oliveira
authors: CO
authors: Miranda
authors: Carla Andreia
authors: CA
authors: Teixeira
authors: Márcia Almeida
authors: MA
authors: Liz
authors: Vera Filipe
authors: VF
authors: Sousa
authors: Filipa
authors: F
authors: Franquinho
authors: Giancarlo
authors: G
authors: Forte
authors: Paolo
authors: P
authors: Di Nardo
authors: Perpétua
authors: P
authors: Pinto-Do-Ó
authors: Mónica Mendes
authors: MM
authors: Sousa
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D026121:Indole Alkaloids / Q000494:pharmacology; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone