Stem Cells, Regenerative Medicine, and Animal Models of Disease

Dennis A. Steindler

Abstract

The field of stem cell biology and regenerative medicine is rapidly moving toward translation to clinical practice, and in doing so has become even more dependent on animal donors and hosts for generating cellular reagents and assaying their potential therapeutic efficacy in models of human disease. Advances in cell culture technologies have revealed a remarkable plasticity of stem cells from embryonic and adult tissues, and transplantation models are now needed to test the ability of these cells to protect at-risk cells and replace cells lost to injury or disease. With such a mandate, issues related to acceptable sources and controversial (e.g., chimeric) models have challenged the field to provide justification of their potential efficacy before the passage of new restrictions that may curb anticipated breakthroughs. Progress from the use of both in vitro and in vivo regenerative medicine models already offers hope both for the facilitation of stem cell phenotyping in recursive gene expression profile models and for the use of stem cells as powerful new therapeutic reagents for cancer, stroke, Parkinson's, and other challenging human diseases that result in movement disorders. This article describes research in support of the following three objectives: (1) To discover the best stem or progenitor cell in vitro protocols for isolating, expanding, and priming these cells to facilitate their massive propagation into just the right type of neuronal precursor cell for protection or replacement protocols for brain injury or disease, including those that affect movement such as Parkinson's disease and stroke; (2) To discover biogenic factors—compounds that affect stem/progenitor cells (e.g., from high-throughput screening and other bioassay approaches)—that will encourage reactive cell genesis, survival, selected differentiation, and restoration of connectivity in central nervous system movement and other disorders; and (3) To establish the best animal models of human disease and injury, using both small and large animals, for testing new regenerative medicine therapeutics.

Key Words: drug discovery; human therapeutics; recursive gene profiling; regenerative medicine; stem cell; transplantation

Introduction

Stem cells have the propensity to produce tissue, an attribute that not only contributes to normal human development but also can lead to oncogenic transformation and hyperplasia (Gibbs et al. 2005; Ignatova et al. 2002; Steindler 2006). Two characteristics of stem (and progenitor) cells reveal their dual nature: (1) "poiesis" (generation) and (2) the overgeneration of cells and tissue (the so-called oncogenic transformation that leads to neoplasia). Because of these particular attributes, there is widespread interest in stem cells and regenerative medicine and their potential to treat and cure human diseases. But controversy and debates surround the question of which cells might be both the best and the most ethically acceptable therapeutic reagents, likewise determining which animal models are indeed the most effective. Animal models of disease are certainly necessary for the regenerative medicine field. Clinical trials of adult (e.g., bone marrow or cord blood transplantation) as well as fetal stem or progenitor cells have already demonstrated the efficacy of such regenerative medicine cell therapies for protecting, repairing, and replacing at-risk cells and tissues (Bjorklund 2005; Reier 2004; Press Release, Yahoo! Finance, November 15, 2006). Yet there is also a daunting side to the emerging field of regenerative medicine. Great expectations and desperate hope for immediate clinical application have driven intense debates at the state level, and international hearings to establish guidelines also try to respond to demands from different citizen groups with disparate agendas. The situation has also prompted patients all over the world to seek alternative and usually unproven stem cell "therapies" that can put them at risk. These challenges justify support for more science that must include both in vitro and in vivo studies of stem/progenitor cells from a variety of tissues and organs.

This article describes advances to date in the use of cells and animal models in regenerative medicine, expectations for future discoveries of the best stem and progenitor cell populations from different tissues and organs, and how in vitro high-throughput screening (HTS¹) bioassays might best utilize the potency of embryonic, fetal, and adult stem cells. The article also describes uses of modeling, in vitro studies, and dynamic stem cell and biogenic stem cell factor screening that could lead to more rapid developments in translational regenerative medicine. The reasoning below suggests that research in regenerative biology and regenerative medicine, although human-centric because of the eventual need for cells from a variety of human tissues and organs at different stages of development and aging, nonetheless requires animals, both as sources of immature cells and as recipients for cell and engineered tissue grafts to establish therapeutic proof-of-principle for any new cell or drug therapy. In vitro bioassay screening and use of simpler organisms could reduce the need for experimentation with mammalian models once researchers better understand the nature of different stem/progenitor cell populations and also further refine HTS. Thus, it is worthwhile to further develop cell culture assays, explore virtual gene and protein screens, and establish standardized and efficient rodent and other animal models of human disease to generate universal bioassays that can be used to establish the required safety and efficacy of any potential new regenerative medicine therapy before going on to human clinical trials. In particular, immunocompromised animals with diseased and injured tissues should continue to host human cell transplants, and investigators should continue to test new drugs gleaned from studies of the bioactive compounds associated with the growth and differentiation of stem cells in the same animal models.

There is no question that animal models of stem cell research in support of regenerative medicine will facilitate rapid translation to the bedside. The regenerative medicine field will continue to foster respect for the animal kingdom amid a pressing need to find new cures for human suffering. With the remarkable paradigm shift that has occurred in scientists' understanding of human self-regenerative potential, there is a high level of confidence that stem cell biology and regenerative medicine will lead to exceptionally effective new therapeutics for movement disorders and all other neurological challenges in the not too distant future.

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