tissues. The low efficiency indicates that, in the short-term, bone marrow and cord blood transplantation are unlikely to be optimal sources for regeneration of nonhematopoietic tissues. However, a number of strategies are being developed to improve the efficiencies with the long-term aim of using hematopoietic cell sources in therapy of nonhematopoietic disease.

INTRODUCTION

The stem cell field has witnessed an explosion of interest in the past 5 years, due to the tandem discoveries of human embryonic stem (hES) cells and reports of the potentially broad differentiation capacity of adult stem cells. In particular, the differentiation capacity of hematopoietic stem cells (HSC), primarily derived from the bone marrow (BM), has been a focus of interest. If, indeed, HSC can differentiate outside of hematopoietic lineages, then BM or cord blood (CB) transplantation could potentially be used for therapeutic applications far beyond those currently used, which are almost exclusively hematologic disorders.

In this analysis, I will discuss the evidence for and against the concept that HSC may generate nonhematopoietic tissues. At this point in time, the literature in this general area is extensive. I will not attempt to review it comprehensively, as there are a number of excellent reviews in the field. Instead, I will endeavor to concisely summarize the data, using a few key papers as examples for the field. Because the majority of the work has been performed with HSC derived from BM, these will be the basis of the majority of the discussion. However, I will also discuss possible differences between BM- and cord CB-derived HSCs toward the end of this appendix.

POTENTIAL NONHEMATOPOIETIC DIFFERENTIATION FROM BONE MARROW CELLS

After Bone Marrow Transplantation

One of the first reports to suggest that hematopoietic cells could generate nonhematopoietic tissue came from the observation that when a whole BM transplant was given to lethally irradiated recipient mice, and skeletal muscles of those animals were subsequently acutely injured, donor-derived cell nuclei were found incorporated into the regenerated skeletal muscle at a frequency of around 0.01 percent [1]. The donor BM was derived from a transgenic mouse strain that expressed lacZ under a nuclear-localized muscle-specific promotor, and the evidence for bona fide incorporation of BM cells into differentiated skeletal muscle was extremely convincing. A number of other studies, using BM transplants in mice, rats, and humans,



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