Brain as the Sea of Marrow.

Most readers are aware of the growing number of controversial reports on the plasticity of adult tissue-derived stem cells. Neural stem cells can repopulate the bone marrow (Bjornson et al., 1999) and bone marrow can give rise to brain cells (Sanchez-Ramos, 2002). The most versatile tissue appears to be bone marrow, which contains cells capable of changing into unexpected phenotypes such as skeletal, smooth and cardiac muscle, liver, and neural cells. Although the experimental findings are novel and intriguing, the idea of marrow cells contributing to brain parenchyma is an old one. The Yellow Emperors Book of Chinese Medicine referred to brain as a “sea of marrow” (Morse, 1938). According to this concept, the vital energy (Chi) originates in the gonads, flows through the bone marrow and empties into the sea of marrow, the brain. To the Western scientist, this philosophical view is as alien as the emerging evidence that adult bone marrow cells can metamorphose into brain cells. Since 1997, an increasing number of independent reports demonstrate that bone marrow cells can differentiate into cells that are not part of their normal repertoire such as skeletal and cardiac muscle, hepatocytes, glia, and neurons (Eglitis and Mezey, 1997; Lee et al., 1995; Azizi et al., 1998; Ferrari et al., 1998; Jackson et al., 2001; Kohyama et al., 2001; Orlic et al., 2001a, 2001b; Petersen et al., 1999; Sanchez-Ramos et al., 2002). The evidence includes in vivo studies in which intravascular infusion or administration of bone marrow directly into brain resulted in transformation of a small proportion of bone marrow cells into glia and neurons. The more elegant experiments relied on replacing bone marrow of lethally irradiated mice (or mice with a genetic defect in hematopoiesis) with bone marrow from a different sex and strain of mouse or with bone marrow from transgenic mice that express green fluorescent protein (GFP) (Brazelton et al., 2000; Mezey et al., 2000). In female mice rescued with male bone marrow transplants, 0.3–2.4% of the recipients’ neurons bore the Y chromosome and these were distributed evenly across all brain regions (Mezey et al., 2000). Another study, using GFP bone marrow grafts reported that 0.2–0.3% of the neurons in olfactory bulb were derived from bone marrow (Brazelton et al., 2000). More recently, several studies have examined the brains of human subjects who previously received bone marrow transplants from sex-mismatched donors. Careful screening of brain sections from females revealed about 0.1% of the Purkinje cells carried the Y chromosome, suggesting that the donor male bone marrow cells had migrated-to brain, where they changed into a neuronal phenotype (Weimann et al., 2003). In a similar study of four human females, the frequency of transformation of the bone marrow to neurons was also very small. For example, the youngest patient (2 years old) who also lived the longest time after transplantation, had the greatest number of marrow-derived neurons (7 in 10,000). Bone marrow contributes to other tissues and includes a surprising number of unexpected phenotypes: oral mucosal cells, smooth muscle cells in atherosclerotic plaques, and cardiomyocytes in humans who had earlier received therapeutic bone marrow transplants (Caplice et al., 2003; Deb et al., 2003). The process most favored by those who doubt the pluripotentiality of bone marrow postulates that fusion of bone marrow cells with host tissue accounts for the apparent “transdifferentiation” of bone marrow cells. In cell coculture experiments, embryonic stem cells were shown to fuse with either bone marrow cells or neural stem cells (Terada et al., 2002,Ying et al., 2002). By this process, the bone marrow cells or the neural stem cells acquired the pluripotential properties of the embryonic stem cells with which they fused. Two recent reports clearly show that fusion accounts for the recovery of liver function and structure * Corresponding author. University of South Florida, 12901 Bruce B. Downs Blvd. MDC 55, Tampa, FL 33612. E-mail address: jsramos@hsc.usf.edu (J. Sanchez-Ramos). R Available online at www.sciencedirect.com