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To circumvent this limitation of BM transplantation, we assessed whether i.v. delivery of immortalized EGFP+ BM-derived murine mesenchymal stromal cells (BM-MSCTERT-EGFP) targets the PNS of a Krabbe's disease model, the Twitcher mouse. In vitro, BM-MSCTERT-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-MSCTERT-EGFP i.v. delivery following sciatic nerve crush, a model of axonal regeneration. Reiterating the in vivo findings, in a coculture system, BM-MSCTERT-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-MSCTERT-EGFP and induced in neighboring Schwann cells. In vivo, BM-MSCTERT-EGFP surmounted the effect of K252a, indicating their ability to act through a neurotrophin-independent mechanism. In summary, i.v. delivery of BM-MSCTERT-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.<\/jats:p>","DOI":"10.1002\/stem.724","type":"journal-article","created":{"date-parts":[[2011,9,6]],"date-time":"2011-09-06T19:07:14Z","timestamp":1315336034000},"page":"1738-1751","source":"Crossref","is-referenced-by-count":24,"title":["Systemic Delivery of Bone Marrow-Derived Mesenchymal Stromal Cells Diminishes Neuropathology in a Mouse Model of Krabbe's Disease"],"prefix":"10.1093","volume":"29","author":[{"given":"Catarina Oliveira","family":"Miranda","sequence":"first","affiliation":[{"name":"Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal"},{"name":"ICBAS-Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar,Universidade do Porto, Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla Andreia","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1rcia Almeida","family":"Liz","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera Filipe","family":"Sousa","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal"},{"name":"ICBAS-Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar,Universidade do Porto, Porto, Portugal"},{"name":"Departamento de Anatomia Patol\u00f3gica, Instituto Polit\u00e9cnico de Sa\u00fade do Norte, Gandra, Paredes, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filipa","family":"Franquinho","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, IBMC-Instituto de Biologia Molecular e Celular,Universidade do Porto, Porto, Portugal"},{"name":"Departamento de Anatomia Patol\u00f3gica, Instituto Polit\u00e9cnico de Sa\u00fade do Norte, Gandra, Paredes, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Forte","sequence":"additional","affiliation":[{"name":"Laboratorio Cardiologia Molecolare & Cellulare, Dip. 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