Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Abstract

Background Microglia, the primary resident myeloid cells of brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e. monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1, and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain-region dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripheral derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

Modeling CSF‐1 receptor deficiency diseases – how close are we?

“…An alternative approach, of transplantation of genetically-engineered autologous hematopoietic stem cells, has proven to be beneficial in X-linked adrenoleukodystrophy [115,116]. Recently strategies for efficient microglial replacement therapy have been developed in mouse [117][118][119].…”

Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients

“…In addition, cognitive and synaptic defects in mice with long-term colonization of marrow derived macrophages in the CNS has also been reported. 44 Despite these limitations, the future of MRT looks promising with recent advances in minimizing transplant toxicity, enhancing the efficiency of cellular engraftment, and using genetically modified donor stem cells. For example, a combination of pre-transplant microglial depletion via CSF1R inhibition and conditioning has yielded >92% donor cell engraftment in murine models of MRT.…”