Organ Replacement Technologies: A New Frontier

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Sutherland DE. Technologies for organ replacement therapy: Competing or complimentary? Presented at AST Seventh Annual Winter Symposium: Approaches to the Replacement of Organ Function; February 13-16, 2003; Naples, Florida.
Watson JT. Toward a totally implantable artificial heart. Presented at AST Seventh Annual Winter Symposium: Approaches to the Replacement of Organ Function; February 13-16, 2003; Naples, Florida.
Rose EA. Advances in cardiac assist/replacement. Presented at AST Seventh Annual Winter Symposium: Approaches to the Replacement of Organ Function; February 13-16, 2003; Naples, Florida.
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Griffith BD. Toward an implantable lung. Presented at AST Seventh Annual Winter Symposium: Approaches to the Replacement of Organ Function; February 13-16, 2003; Naples, Florida.
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Atala AJ. Stem cells, nuclear transfer, and tissue engineering: Challenges and opportunities. Presented at AST Seventh Annual Winter Symposium: Approaches to the Replacement of Organ Function; February 13-16, 2003; Naples, Florida.
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Stem Cells Potentially Useful in Many Organ Systems

The therapeutic promise of human embryonic stem cells (hESCs) is as pluripotential as are the cells themselves, according to Thomas B. Okarma, PhD, MD,^[11] of Geron Corporation in Menlo Park, California. Because these cells can differentiate into all 3 developmental germ layers (ectoderm, endoderm, and mesoderm), they can give rise to virtually any cell type. Further advantages include stability, normal karyotype, characteristic markers, and high proliferative capacity. Expression of telomerase by hESCs allows regulation of telomere length, a molecular clock that counts cell divisions. By extending cellular replicative potential, telomerase activity prevents cellular senescence.

Nuclear transplantation (therapeutic cloning) has the potential to provide a limitless source of cells for regenerative therapy. Potential stem cell applications include cardiomyocytes for heart failure, dopaminergic neurons for Parkinson's disease, neural cells for spinal cord injury, and islet cells for diabetes mellitus, although islets are very difficult to generate. Cardiomyocytes developed from stem cells contract spontaneously, express appropriate cell type markers, and express appropriate receptors for cardioactive drugs. Osteoblasts developed from stem cells have been shown to heal fractures in animal models. While not yet useful for liver disease, hepatocytes derived from stem cells facilitate drug discovery research by testing metabolism and toxicity of new compounds. Neuronal hESCs develop synapses, produce a full spectrum of neurotransmitters, and exhibit normal electrophysiology. Engrafted dopaminergic cells have been shown to function and survive in patients with Parkinson's disease, but thus far have not improved patient outcomes. In a rat model of spinal cord injury, transplantation of oligodendrocytes into areas of acute contusion resulted in remyelination and partial functional recovery. These are very compelling data, according to Dr. Okarma.

Potential implications for the field of transplantation include a reduced need for immunosuppression as a result of induction of chimerism with the use of hESC-derived hematopoietic progenitors, or cells that are genetically engineered to be immunologically null. Despite the potential advantages of hESCs, their origination from human embryos has stirred ethical controversy, and availability of human donor eggs is limited. Anthony J. Atala, MD,^[12] an Associate Professor of Surgery at Harvard Medical School and Boston Children's Hospital in Boston, Massachusetts, is studying methods to isolate hESCs without sacrificing human embryos, including amniocentesis and chorionic villus sampling. He stressed the difference between therapeutic and reproductive cloning and the need to educate the public about that difference. Although therapeutic cloning by nuclear transplantation could theoretically provide an unlimited source of cells for regenerative therapy, histocompatibility of the cloned cells is one of the major challenges in transplantation medicine.

To tackle this problem, Dr. Atala's group created bioengineered tissues from cardiac, skeletal muscle, and renal cells cloned from adult bovine fibroblasts.^[13] Reverse transcription polymerase chain reaction and western blot analysis confirmed that the cloned tissues expressed tissue-specific mRNA and proteins, but a different mitochondrial DNA haplotype was expressed. Grafts transplanted into the nuclear donor animals were viable in the long term, with no delayed-type hypersensitivity rejection. These grafts included skeletal muscle and cardiac "patches", and functioning renal units with organized glomeruli- and tubule-like structures that concentrated urea nitrogen and creatinine.

Donor cells are easier to obtain but present immunologic challenges, while autologous cells are more difficult to obtain yet impose no immunologic barriers. Cell sources include differentiated and undifferentiated cells, pluripotent progenitor cells, and embryonic stem cells. Adult or fetal differentiated cells cannot be expanded, but undifferentiated unipotent progenitor cells can be expanded under the right growth conditions. Pluripotential cells, including bone marrow, fat, and skin cells, have limited growth potential. Embryonic stem cells can also be found naturally in teratomas. "I still believe the best option is to go to the patient's own native tissue, but there is a menu of choices in cases where there this is not an option," Dr. Atala said.