Cell Biology, Neurobiology & Anatomy

Education:
PhD, Biocenter of the University of Basel, 1976
Postdoctoral, The Johns Hopkins University, Baltimore, 1981

Graduate Programs:
Program in Cell and Developmental Biology
Program in Neuroscience

Research Area: Mechanisms of neural crest stem cell differentiation. Mechanisms of differentiation of epidermal neural crest stem cells (EPI-NCSC) and their application in animal models of human disease. Translational research. Regenerative medicine.

The neural crest is a transitory tissue of the vertebrate embryo that originates in the neural folds. Neural crest stem cells leave the forming neural tube and migrate to diverse locations in the embryo where they generate a wide array of cell types and tissues. They give rise to the autonomic and enteric nervous systems, to most primary sensory neurons and to endocrine cells, such as the adrenal medulla and calcitonin-producing cells of the thyroid gland. Neural crest cells also contribute to the smooth musculature of the cardiac outflow tract and the great vessels. In addition, they give rise to the cranial mesenchyme. The cranial mesenchyme generates cartilage, bone and connective tissue of the face and ventral neck, tooth papillae, meninges and the corneal stroma. Many birth defects, familial diseases and malignancies are of neural crest origin. Recently, we have discovered adult neural crest stem cells, termed 'epidermal neural crest stem cells' (EPI-NCSC), in the bulge region of hair follicles. As embryonic remnants in an adult location, they combine many advantages of embryonic stem cells and adult stem cells. Similar to embryonic stem cells, they have an innate capability to generate a multitude of cell types. EPI-NCSC can be isolated from bulge explants as a highly pure population of multipotent stem cells, and they can be expanded in culture into millions of cells without losing stem cell markers. Similar to other adult stem cells, they are easily accessible by minimal invasive procedure. Moreover, the patients' own EPI-NCSC could be used for transplantation, which avoids graft rejection. Finally, by harvesting EPI-NCSC no one gets harmed.

In a mouse model of spinal cord injury, EPI-NCSC showed several desirable traits. Acutely grafted EPI-NCSC survived and integrated into the spinal cord. They did not migrate within the spinal cord, but remained at the site of transplantation. They did not proliferate, and they did not form tumors. Subsets expressed markers for neurons, including a marker for GABAergic neurons. GABAergic neurons are important components of the spinal 'central pattern generator', a neural network that is involved in left/right ambulation. It will therefore be important to determine whether EPI-NCSC grafts in the lesion can lead to an improvement of spinal reflexes. Other subsets of EPI-NCSC in spinal cord grafts express markers for oligodendrocytes, but not for astrocytes. Oligodendrocytes are nerve supporting cells that myelinate axons. Myelination is critical for proper nerve function.

Gene profiling of embryonic neural crest cells and EPI-NCSC has yielded important data and is a freely available resource for future mouse neural crest research (http://www.ncbi.nlm.nih.gov/geo, series number GSE4680). We found that, as expected, embryonic neural crest cells and EPI-NCSC have a similar gene profile. Accordingly, we have defined a 'neural crest stem cell molecular signature'. This panel of signature genes is abundantly expressed by both embryonic neural crest stem cells and EPI-NCSC, but not by epidermal stem cells with which they share the niche. By applying the molecular signature to published markers and gene profiles, we found that EPI-NCSC are distinctly different from other types of known skin-resident stem cells/progenitors.

Multipotent adult stem cells, such as EPI-NCSC, are attractive candidates for future therapeutic applications.