Systemic Delivery of Bone Marrow-Derived Mesenchymal Stromal Cells Diminishes Neuropathology in a Mouse Model of Krabbe's Disease

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Miranda, CO (Author) Other; Teixeira, CA (Author) Other; Liz, MA (Author) Other; Sousa, VF (Author) Other; Franquinho, F (Author) Other; Forte, G (Author) Other; Di Nardo, P (Author) Other; Perpetua Pinto do O (Author) FEUP; Monica M Sousa (Author) ICBAS

Journal

Title: Stem Cells

Vol. 29

Pages: 1738-1751

ISSN: 1066-5099

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 19 Citations

Scopus - 20 Citations

Other information

Authenticus ID: P-002-K5T

DOI: 10.1002/stem.724

Abstract (EN): 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 out-growth 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. STEM CELLS 2011;29:1738-1751

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14