Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains

Abstract

Stem cells are a valuable resource for treating disease, but limited access to stem cells from tissues such as brain restricts their utility. Here, we injected marrow stromal cells (MSCs) into the lateral ventricle of neonatal mice and asked whether these multipotential mesenchymal progenitors from bone marrow can adopt neural cell fates when exposed to the brain microenvironment. By 12 days postinjection, MSCs migrated throughout the forebrain and cerebellum without disruption to the host brain architecture. Some MSCs within the striatum and the molecular layer of the hippocampus expressed glial fibrillary acidic protein and, therefore, differentiated into mature astrocytes. MSCs also populated neuron rich regions including the Islands of Calleja, the olfactory bulb, and the internal granular layer of the cerebellum. A large number of MSCs also were found within the external granular layer of the cerebellum. In addition, neurofilament positive donor cells were found within the reticular formation of the brain stem, suggesting that MSCs also may have differentiated into neurons. Therefore, MSCs are capable of producing differentiated progeny of a different dermal origin after implantation into neonatal mouse brains. These results suggest that MSCs are potentially useful as vectors for treating a variety of central nervous system disorders.Stem cells are characterized by a capacity to self-renew and to generate progeny capable of differentiating into multiple yet distinct cell lineages. Although stem cells derived from early embryos can differentiate into all somatic cell types (1-3), those derived from adult tissues are thought to produce only the cell lineages characteristic of the tissues wherein they reside. For example, hematopoietic stem cells resident in bone marrow give rise to only blood elements (4). Stem cells also have been identified in the gut, gonads, skin, and brain of adults (5, 6). Neural stem cells have been proposed as useful vectors for treating diseases of the central nervous system, but their lack of accessibility limits their utility.Recently, several reports demonstrated that some stem cells may have greater plasticity than previously envisioned. Eglitis and Mezey reported that a few donor cells from bone marrow transfused into immunodeficient mice were recovered as macroglia in the host brain (7). However, the nature of the marrow cells that engrafted in brain was not determined. Azizi et al. (8) infused rat brains with human marrow stromal cells (MSCs) that are capable of expansion, self-renewal, and differentiation into multiple mesenchymal cell lineages (9, 10). The human MSCs migrated in brain in a manner similar to paraventricular astrocytes, but whether the cells adopted neural cell fates was not defined. In related experiments, Bjornson et al. showed that neural stem cells differentiated into myeloid and lymphoid cell lineages after transplantation into the hematopoietic system of irradiated hosts (11). Together, these findings suggest that it may be possible to reconsti...

Human Bone Marrow Stem Cells Exhibit Neural Phenotypes and Ameliorate Neurological Deficits after Grafting into the Ischemic Brain of Rats

“…Previous in vivo studies have examined the differentiation of murine MSC. Transplantation of murine MSCs gave rise to neurons (8,29,35) and astrocytes (29). Two recent reports have shown that human MSCs could differentiate in vitro into neurons (49,57) and astrocytes (49).…”

“…Bone marrow stromal cells or mesenchymal stem cells (MSCs) not only give rise to mesodermal lineage cells such as osteoblasts, chondrocytes, adipocytes, and muscle cells (4,13,29,55,33), but also adopt neuroectodermal cell fate. It has been shown that donor-derived neurons and astrocytes are found in host rodent brain following transplantation of rodent bone marrow (8,14,29,35). However, it is not known if transplantation of MSCs into the brain can be beneficial in treating neurological disorders.…”

Migration, fate and in vivo imaging of adult stem cells in the CNS

“…In some studies, they differentiated in vivo into astrocytes and even neurons. 47,48 Human MSCs were injected into rats after middle cerebral artery occlusion. 49,50 In both studies, implanted cells reduced the lesion volume and elicited functional improvement compared with the control sham group.…”

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

“…14 Marrow stromal cells (MSCs) normally give rise to bone, cartilage, and mesenchymal cells (reviewed in La Russa et al 15 ). Isolation of MSCs that can differentiate to brain cells, such as glial cells 16 and neural cells, 17 has been demonstrated. Infusion of human MSCs into rat striatum resulted in engrafting, migration, and survival of the cells.…”