Brain to blood blood to brain

Adult neurons were at one time thought to have a limited ability to be replaced. However, recent studies have suggested that the adult central nervous system has a considerable capacity to repair itself following injury. In 1999, Doetsch et al. identified NSCs in the subventricular zone, which produces neuroblasts that migrate to the olfactory bulb (36). This region has been described as brain marrow because, similar to bone marrow, it is a region of cell proliferation and neurogenesis (37). Murine NSCs give rise to all germ layers when injected into chick blastocysts, suggesting that these stem cells have a wide repertoire of possible fates (38). In addition, oligo-dendrocyte precursor cells, responding to external signals in culture, have been shown to revert to cells with the phenotype of neutral stem cells (39).

Unlike hematopoietic stem cells, which do not replicate in culture and lose their ability to self-renew, NSCs can be grown in culture, where they produce structures called neurospheres (40). Neurospheres contain cells that can produce all of the different cell types that constitute normal brain. In studying the behavior of neurospheres, the capacity of the cells from these structures to produce blood was observed.

In one such study by Bjornson et al. (41), cells for transplant were derived from tissue containing NSCs isolated from fetal brain and cultured and, in separate experiments, from clonally derived NSC cell lines. Neurospheres from prospectively isolated fetal NSCs were grown in epidermal growth factor and basic fibroblast growth media. Donor animals and NSC cell lines were derived from ROSA26 animals, that are transgenic for lacZ. Contribution of the donor NSCs to the recipient blood was determined using H-2kb, which is expressed by hematopoietic cells of donor origin (ROSA26), but not of recipient (BALB/c) origin. Donor-derived engraftment was observed in 100% of bone marrow recipients, 100% of embryonic NSC recipients, 70% of adult NSC recipients, and 63% of the clonal adult NSC recipients. Between 35 and 65% of CD45-positive hematopoietic cells were donor derived, regardless of whether initial tissue came from adult brain or embryonic brain. Donor-derived hematopoietic cells were present in the blood 5 to 12 mo posttransplant. Repopulation of the immune system after neural cell transplant took an average of 3 wk longer than after bone marrow transplant.

The authors (40,41) proposed that the conversion of neural cells to hematopoietic lineages does not occur immediately, or that NSCs proliferate more slowly than hematopoietic stem cells. However, these studies involved the culture of heterogeneous tissue following transplant, and it is unclear which cell from this mixture produced blood. A subsequent attempt to replicate this result was unable to show production of blood from NSCs (neurospheres), and the authors suggested that epigenetic changes or mutations need to occur for these cells to have hematopoietic potential that exhibits plasticity (42).

Other studies have focused on the ability of bone marrow-derived cells to contribute to the brain. In one such study, Eglitis and Mezey (43) showed data to suggest that unfractionated bone marrow contributes to micro- and macroglia following bone marrow transplant in mice. Donor contribution was determined either by retrovirally tagged cells or by the Y chromosome in sex-mismatched transplants. Recipient animals in this study had defective steel-factor receptors and, as a result, defective hematopoietic stem cells. This provides the transplanted stem cells with a competitive advantage for engraftment. In this study, donor-derived glial cells were present as early as 7 d following transplant, and these cells increased in number during the posttransplant period. Previously, it was unknown whether these glial cells were derived from neural progenitors or whether they had a hematologic origin, so it is unclear whether this activity should be considered plasticity. Furthermore, it is unclear whether these cells were functional, and whether the mutant background of the recipient animals had any effect on the engraftment of these cells within the brain.

In a study that similarly used mutant recipient animals, Mezey et al. (44) studied the ability of bone marrow-derived cells to produce neurons in PU.1 null mice following bone transplant. PU.1 is a transcription factor expressed y1..

Fig. 3. Human multipotent astrocytic stem cells. (Figure courtesy Dennis Steindler.)

Fig. 3. Human multipotent astrocytic stem cells. (Figure courtesy Dennis Steindler.)

exclusively in blood. Knockout mice fail to produce macrophages, neutrophils, mast cells, osteoclasts, and B and T cells at birth. These animals require bone marrow transplant in the first 48 h of life to survive and develop. FISH analysis for Y chromosome, with concomitant immunohistochemistry to identify cells containing NeuN, a nuclear protein found exclusively in neurons, were used to determine donor-derived contribution to neurons. At 1-4 mo of age, animals were sacrificed and examined for donor-derived tissue. Overall, between 2 and 4% of cells in the brain were Y chromosome-positive, with less than 1% of the neurons donor derived. Areas with the highest frequency of donor-derived cells were within the choroid plexus, ependyma, and subarachnoid space, suggesting that the site of entry of these cells from the bloodstream is the cerebrospinal fluid.

Questions of brain-blood plasticity would benefit from clonal studies that can clearly demonstrate hematopoietic and neuronal potential from a single, uncultured cell. The recent ability to isolate and purify NSCs prospectively will allow such clonal studies to be performed (45,46) (Fig. 3). The ability of these cells to produce hematopoietic cell fate without prior culture should be determined because it is important to know whether this plasticity is inherent to NSCs or somehow conferred on these cells by a period in culture. Furthermore, it is important to determine the karyotype of the donor-derived cells that result from neurospheres produced in culture because the hematopoietic activity may be the result of a fusion event within the cultured

Fig. 4. Functional blood vessels derived from highly purified, bone marrow-derived stem cells. (Courtesy Edward Scott.) (See color plate 3 in the insert following p. 82.)

tissues. A further question concerns the origin of adult NSCs and whether there is trafficking between the brain marrow and bone marrow (47).

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