In rodents, bone marrow-derived cells enter the brain during adult life. Allogeneic bone marrow transplantation is used to treat genetic CNS diseases, but the fate of human bone marrow and CD34 ؉ cells within the brain remains to be elucidated. The present study demonstrates that cells derived from human CD34 ؉ cells, isolated from either cord blood or peripheral blood, migrate into the brain after infusion into nonobese diabetic͞severe combined immunodeficient mice. Both types of CD34 ؉ -derived cells differentiate into perivascular and ramified microglia. The lentiviral transfer of genes into CD34 ؉ cells before infusion does not modify the differentiation of human CD34 ؉ cells into microglia, allowing new transgenic proteins to be expressed in these cells. The transplantation of CD34 ؉ cells could thus be used for the treatment of CNS diseases. U p to 20% of the total nonneuronal cell population is made of microglia (1). Microglia are ubiquitously distributed in the CNS and play a major role in the response to infectious, traumatic, inflammatory, and ischemic processes, as well as in degenerative CNS diseases, such as Alzheimer's disease, multiple sclerosis, or Parkinson's disease. The adult brain contains two subsets of microglia: the resting microglia, which ramify throughout the brain parenchyma, and the perivascular microglia, which resemble peripheral macrophages (1, 2).Following a long debate about their origin, microglia are now believed to be derived from bone marrow as liver, spleen, or lung macrophages (2). Murine bone marrow-derived cells enter the CNS and differentiate into microglia (3-5). In mice, the turnover of perivascular microglia reaches 30% 1 year after engraftment, whereas the turnover of ramified microglia is much slower (6, 7). However, the subset of bone marrow-derived cells that are the progenitors of microglia has not been characterized. In mice, transplantation of transduced bone marrow cells allows the expression of glucocerebrosidase or GFP in microglia (8, 9). In humans, there are very little data documenting the fate of bone marrow-derived cells in the CNS after bone marrow transplantation (BMT) (10, 11). However, that BMT is used to treat genetic CNS diseases like Hurler disease or X-linked adrenoleukodystrophy (ALD) (12, 13) suggests that bone marrow cells may serve as vehicles for the delivery of genes into the human CNS.Transplantation of CD34 ϩ hematopoietic cells is replacing that of whole bone marrow cells for many applications, including autotransplantation in cancer, non-HLA genoidentical BMT, and gene therapy (14-16). Human CD34 ϩ cells can be easily collected from cord blood at birth or from peripheral blood after cytokine mobilization. We studied the migration, differentiation, and distribution of human CD34 ϩ cells purified either from umbilical cord blood (UCB) or from mobilized peripheral blood (MPB) in the brain of nonobese diabetic͞severe combined immunodeficient (NOD͞SCID) mouse. Our results demonstrate that a fraction of these cells, when infused into NOD͞SCI...

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms, whereas inflammation allegedly plays no role in AMN. How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. To gain insights into these questions, we undertook a transcriptomic approach followed by a functional-enrichment analysis in spinal cords of the animal model of AMN, the Abcd1− null mice, and in normal-appearing white matter of cAMN and cALD patients. We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation, adipocytokine and insulin signaling pathways, and protein synthesis. Functional validation by quantitative polymerase chain reaction, western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase, being VLCFA in excess a causal, upstream trigger promoting the altered signature. We conclude that X-ALD is, in all its variants, a metabolic/inflammatory syndrome, which may offer new targets in X-ALD therapeutics.