Abstract
Human induced pluripotent stem (iPS) cells have the potential to establish a new field of promising regenerative medicine. Therefore, the safety and the efficiency of iPS-derived cells must be tested rigorously using appropriate animal models before human trials can commence. Here, we report the establishment of rabbit iPS cells as the first human-type iPS cells generated from a small laboratory animal species. Using lentiviral vectors, four human reprogramming genes (c-MYC, KLF4, SOX2, and OCT3/4) were introduced successfully into adult rabbit liver and stomach cells. The resulting rabbit iPS cells closely resembled human iPS cells; they formed flattened colonies with sharp edges and proliferated indefinitely in the presence of basic FGF. They expressed the endogenous pluripotency markers c-MYC, KLF4, SOX2, OCT3/4, and NANOG, whereas the introduced human genes were completely silenced. Using in vitro differentiating conditions, rabbit iPS cells readily differentiated into ectoderm, mesoderm, and endoderm. They also formed teratomas containing a variety of tissues of all three germ layers in immunodeficient mice. Thus, the rabbit iPS cells fulfilled all of the requirements for the acquisition of the fully reprogrammed state, showing high similarity to their embryonic stem cell counterparts we generated recently. However, their global gene expression analysis revealed a slight but rigid difference between these two types of rabbit pluripotent stem cells. The rabbit model should enable us to compare iPS cells and embryonic stem cells under the same standardized conditions in evaluating their ultimate feasibility for pluripotent cell-based regenerative medicine in humans.
Highlights
Mammalian pluripotent stem cells are those cells capable of differentiating into all germ layers but not into the extraembryonic tissues
In this early phase of induced pluripotent stem (iPS) generation, we employed a hypoxic (5% O2) culture condition because it was reported that hypoxia enhances the generation of human iPS cells and prevents the differentiation of human embryonic stem (ES) cells [31, 32]
The rabbit iPS cells established in this study fulfilled all of the requirements for the acquisition of the fully reprogrammed state and showed high similarity to their ES cell counterparts
Summary
The rabbit model should enable us to compare iPS cells and embryonic stem cells under the same standardized conditions in evaluating their ultimate feasibility for pluripotent cell-based regenerative medicine in humans. Human iPS cells might represent an ideal source for patient-specific cell-based regenerative medicine They are uniquely distinct in their origin compared with other pluripotent stem cells, and they might express unidentified or uncontrollable characters that do not exist in “normal” ES cells [5,6,7]. We expect that rabbit iPS cells will provide unique, accessible animal models for assessing the efficacy and safety of new iPS-based treatment This rabbit model should enable us to compare iPS cells and ES cells under the same standardized conditions in evaluating their ultimate feasibility for cell-based regenerative medicine
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