Hematopoietic potential within the adult murine central nervous system
Tobias Koeniger1, Süleyman Ergün1, Stefanie Kuerten1,2 1Institute of Anatomy and Cell Biology, Julius-Maximilians University, Würzburg, Germany; 2Institute of Anatomy and Cell Biology, Friedrich-Alexander University, Erlangen-Nürnberg, Germany
Engraftment of microglia-like cells into the central nervous system (CNS) has repeatedly been observed in murine bone marrow (BM) transplantation models. While it has been established that the transferred hematopoietic stem cells (HSC) and progenitors themselves rather than BM-derived monocytes can seed the CNS under specific conditions, this phenomenon has been considered merely as an experimental artifact. However, why are HSCs able to engraft within the CNS while possibly maintaining their stem-cell properties over a long period of time? One explanation could be local niches for physiological HSCs, which were already described within the murine CNS almost 40 years ago. As this possibility has been overlooked in recent studies, we aimed to re-examine these findings in the light of the current state of research. Single cell suspensions were prepared from mouse brains and analyzed in hematopoietic colony-forming assays. Rare cells within the isolate rapidly proliferated and gave rise to colonies that comprised different hematopoietic lineages, predominantly granulocyte and macrophage. Importantly, colonies formed even after excluding intravascular CD45(+) cells via cell sorting, following their in vivo labeling by intravenously injected antibody, which revealed that the colony-forming cells were indeed located behind the CNS blood vessel endothelium. Sorting of CNS macrophages from transgenic Iba1-eGFP mice showed that differentiated Iba1(+) cells slowly proliferated but failed to produce large colonies under the tested conditions, which solely arose from resident CD45(+)Iba1(-) cells. Further sorting experiments confirmed that these cells displayed the hematopoietic progenitor phenotype LIN(-) Sca-1(-) c-Kit(+). Our findings corroborate the existence of hematopoietic potential inside the CNS, which represents an alternative explanation for many BM transfer studies carried out over the last decades. The described progenitors might constitute an on-site source of innate immune cells during CNS injury or even contribute to the physiological turnover of CNS macrophages. Whether this holds true is currently investigated in our laboratory.
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