Introduction

Stem cells can replenish themselves in the long-term while producing progenies that are different from themselves. Stem cells from many sources possess such traits. Stem cells isolated from the inner cell mass (ICM) of a pre-implantation blastocyst,1'2 known as embryonic stem cells (ESCs), can generate all cell lineages that make up an organism. Stem cells isolated from an organ or a tissue generally have restricted potential to produce certain cell types that constitute the organ or tissue. However, precursor cells cultured from many tissues, especially after prolonged expansion, exhibit broader potential and produce cell types that do not belong to the tissue of origin. One example is the bone marrow precursor cells that can produce non-hematopoietic cell types, including neural cells.3 Thus, non-neural stem cells, as well as neural stem cells, may produce neurons.

Neurons are the building blocks of the nervous system. Like cells in nonneural tissues, neurons are born in a highly ordered process from their precursors, neuroepithelia or neural stem cells, with the first birth of projection neurons followed by interneurons and glial cells. Unlike many other cell types, a neuron in one region differs from that in another place even though they may carry the same transmitters. The temporal sequence of neuronal birth and their topographical locations form the basis of the first order of neuronal connections. Environmental (e.g. glia) and target signals subsequently promote functional maturation and shape neuronal circuitry. These stereotypic as well as regulatory rules likely apply to the differentiation of neurons from stem cells in a culture Petri dish and influence the

* Correspondence: Departments of Anatomy and Neurology. The Stem Cell Research Program. The Waisman Center. The WiCell Institute, University of Wisconsin, Madison, WI, USA. Email: [email protected].

application of stem cell-produced neurons in cell therapy. For production of neurons from human stem cells, it may be necessary to explore alternatives to these fundamental rules learned from animal studies.

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