Bone Marrow to Brain: Searching for markers of bone marrow stem cells with neurogenic potential
2001 Senior Scholar in Aging Award

A challenge for the next decade will be to enhance the prospects for the increasing number of elderly afflicted with debilitating neurological diseases: Parkinson's or stroke. We recently discovered that adult bone marrow, transplanted into adult recipients, migrates to the brain and adopts neuronal characteristics. The goal of this proposal is to facilitate therapy by enriching for and enhancing differentiation of the requisite subset of bone marrow cells. This stem cell approach (adult marrow to adult brain) has particular advantages: the patient is his own donor, which overcomes problems such as the immune response, ethical issues, and access to cells.

Researchers
Helen M. Blau Ph.D.
Stanford University School of Medicine

Dr. Blau is studying the contributions of bone marrow stem cells to tissues in both mouse and man. She has demonstrated that the transition of bone marrow derived cells into muscle is a two-step process. First, bone marrow derived cells migrate to and occupy the muscle stem cell compartment. Then, in response to stress (exercise), these cells can expand and integrate into muscle fibers. Dr. Blau also has shown that in adult human brains, bone marrow derived cells can contribute to mature Purkinje neurons. These neurons are large and complex cells in the cerebellar cortex, critical to movement and balance. When cell fusion occurs between a bone marrow derived cell and a mature neuron, previously silent Purkinje genes are activated in the marrow nucleus, suggesting that this fusion event could serve as a means of rescuing damaged brain cells.

Dr. Blau reports: These studies have focused on several important aspects of neuronal gene regulation and cellular reprogramming. First, we have increased our understanding of the biological mechanisms that allow bone marrow-derived cells (BMDC) to contribute to Purkinje neuron regeneration. We have shown that these cells contribute to Purkinje cells when the immune response is challenged by dermatitis or by a graft versus host reaction. Second, using heterokaryons we have investigated the molecular mechanisms underlying reprogramming of BMDC nuclei for neuronal cell fates. In studies of reprogramming in Purkinje cells, we have developed a means of performing BMT in neonatal mice using rat bone marrow. In conjunction with laser capture microscopy we are able to analyze the extent of BMDC nuclear reprogramming for a Purkinje cell fate. These studies show that somatic neural cells have the molecular machinery required for reprogramming, and that heterokaryon formation may have practical applications, bypassing the use of embryonic stem cells.

Finally, using protein-protein interaction, protein-localization and siRNA technologies developed in our laboratory, we are advancing our understanding of gene regulation during neurogenesis and myogenesis in the course of nuclear reprogramming.