PMID- 23809254 OWN - NLM STAT- MEDLINE DCOM- 20141029 LR - 20181202 IS - 1555-3892 (Electronic) IS - 0963-6897 (Linking) VI - 23 IP - 2 DP - 2014 Feb TI - Primary bone marrow mesenchymal stromal cells rescue the axonal phenotype of Twitcher mice. PG - 239-52 LID - 10.3727/096368913X669752 [doi] AB - Krabbe's disease (KD) is a demyelinating disorder caused by the deficiency of lysosomal galactocerebrosidase (GALC), affecting both the central (CNS) and the peripheral nervous system (PNS). A current therapy, hematopoietic stem cell transplantation (HSCT), is ineffective at correcting the PNS pathology. We have previously shown that systemic delivery of immortalized bone marrow-derived murine mesenchymal stromal cells (BM-MSCs) diminishes the neuropathology of transplanted Twitcher mice, a murine model of KD. In this study, to move one step closer to clinical application, the effectiveness of a systematic delivery of primary BM-MSCs to promote recovery of the Twitcher PNS was assessed. Primary BM-MSCs grafted to the Twitcher sciatic nerve led to increased GALC activity that was not correlated to decreased psychosine (the toxic GALC substrate) accumulation. Nevertheless, BM-MSC transplantation rescued the axonal phenotype of Twitcher mice in the sciatic nerve, with an increased density of both myelinated and unmyelinated axons in transplanted animals. Whereas no increase in myelination was observed, upon transplantation an increased proliferation of Schwann cell precursors occurred. Supporting these findings, in vitro, BM-MSCs promoted neurite outgrowth of Twitcher sensory neurons and proliferation of Twitcher Schwann cells. Moreover, BM-MSCs expressed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and promoted increased BDNF synthesis by neighboring Schwann cells. Besides their action in neurons and glia, BM-MSCs led to macrophage activation in Twitcher sciatic nerves. In summary, primary BM-MSCs diminish the neuropathology of Twitcher sciatic nerves by coordinately affecting neurons, glia, and macrophages. FAU - Miranda, Catarina Oliveira AU - Miranda CO AD - Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal. FAU - Teixeira, Carla Andreia AU - Teixeira CA FAU - Sousa, Vera Filipe AU - Sousa VF FAU - Santos, Telma Emanuela AU - Santos TE FAU - Liz, Marcia Almeida AU - Liz MA FAU - Marques, Ana Maio AU - Marques AM FAU - Pinto-do-O, Perpetua AU - Pinto-do-O P FAU - Sousa, Monica Mendes AU - Sousa MM LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130627 PL - United States TA - Cell Transplant JT - Cell transplantation JID - 9208854 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (brain-derived growth factor) RN - 0 (enhanced green fluorescent protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 2238-90-6 (Psychosine) RN - 9061-61-4 (Nerve Growth Factor) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cells, Cultured MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Green Fluorescent Proteins/metabolism MH - Male MH - Mesenchymal Stem Cells/*cytology/metabolism MH - Mice, Transgenic MH - Nerve Growth Factor/metabolism MH - Psychosine/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction EDAT- 2013/07/03 06:00 MHDA- 2014/10/30 06:00 CRDT- 2013/07/02 06:00 PHST- 2013/07/02 06:00 [entrez] PHST- 2013/07/03 06:00 [pubmed] PHST- 2014/10/30 06:00 [medline] AID - ct0689miranda [pii] AID - 10.3727/096368913X669752 [doi] PST - ppublish SO - Cell Transplant. 2014 Feb;23(2):239-52. doi: 10.3727/096368913X669752. Epub 2013 Jun 27.