The remarkable plasticity of marrow stromal cells (MSCs) after transplantation to models of neurological disease and injury has been described. In this report, we investigated the plasticity and long-term survival of MSCs transplanted into the normal brain. MSCs were isolated from green fluorescent protein (GFP) transgenic rats and double-labeled with 5-bromo-2-deoxyuridine (BrdU) and bis benzamide (BBZ) prior to transplantation into the adult hippocampus or striatum. Surgery elicited an immediate inflammatory response. MSC grafts were massively infiltrated by ED1-positive microglia/macrophages and surrounded by a marked astrogliosis. By 14 days, graft volume had retracted and GFP immunoreactivity was absent, indicating complete donor rejection. Consequently, MSCs did not exhibit plasticity formerly identified in other studies. However, BrdU-and BBZ-labeled cells were detected up to 12 weeks. Control transplants of nonviable MSCs demonstrated the transfer of donor labels to host cells. Unexpectedly, BrdU labeling was colocalized to host phagocytes, astrocytes, and neurons in both regions. Our results indicate that MSCs transplanted to the intact adult brain are rejected by an inflammatory response. Moreover, use of the traditional cell labels BrdU and BBZ may provide a misleading index of donor survival and differentiation after transplantation. STEM CELLS 2006;24:2483-2492

We recently differentiated adult rat and human bone marrow stromal cells (MSCs) into presumptive neurons in cell culture. To determine whether the MSCs assume neuronal functions in vivo, we now characterize for the first time engraftment, migration, phenotypic expression, and long-term survival after infusion into embryonic day 15.5 (E15.5) rat ventricles in utero. By E17.5, donor cells formed discrete spheres in periventricular germinal zones, suggesting preferential sites of engraftment. The cells expressed progenitor vimentin and nestin but not mature neuronal markers. By E19.5, a subset assumed elongated migratory morphologies apposed to radial nestin-positive fibers running through the cortical white matter and plate, suggesting migration along radial glial processes. Cells remaining in germinal zones extended long, vimentin-positive fibers into the parenchyma, suggesting that the MSCs generated both migratory neurons and guiding radial glia. Consistent with this suggestion, Ͼ50% of cultured mouse MSCs expressed the neuroprecursor/radial glial protein RC2. From E19.5 to postnatal day 3, MSCs populated distant areas, including the neocortices, hippocampi, rostral migratory stream, and olfactory bulbs. Whereas donor cells confined to the subventricular zone continued to express nestin, cells in the neocortex and midbrain expressed mature neuronal markers. The donor cells survived for at least 2 months postnatally, the longest time examined. Confocal analysis revealed survival of thousands of cells per cubic millimeter in the frontal cortex and olfactory bulb at 1 month. In the cortex and bulb, 98.6 and 77.3% were NeuN (neuronal-specific nuclear protein) positive, respectively. Our observations suggest that transplanted adult MSCs differentiate in a regionally and temporally specific manner.

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Purpose Brentuxiumab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate approved in 2011 for treating anaplastic large cell and Hodgkin lymphomas. The product label indicates that three BV-treated patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC-virus induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. We report 5 patients who developed BV-associated PML, including two immunocompetent patients. Patients Case information was obtained from clinicians (four patients) or a Food and Drug Administration database (one patient). Results All five patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of three BV doses (range, 2 to 6) and within a median of 7 weeks following BV initiation (range, 3 to 34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in cerebrospinal fluid (two patients), or CNS biopsy (three patients); and brain MRI scans with white matter abnormalities (five patients). Four patients died a median of 8 weeks (range, 6 to 16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. Conclusion PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop following BV initiation. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.