The reprogramming of fibroblasts into iPS stem cells via modified proteins was first reported in a landmark publication in Cell Stem Cell in 2009. The new technique, which involved only four genetically engineered proteins, had the potential to lead to the first clinic-ready human induced pluripotent stem (iPS) cells. The majority of human iPSC (hiPSC) lines to date had been generated using lentiviral and retroviral methods, which are known to generate multiple chromosomal integrations and possible genetic dysfunction. This new protein-based method eliminates the potential risks associated with the use of viruses, DNA transfection, and potentially harmful chemicals. Using the new method, protein-based reprogrammed iPS cells were able to be maintained for more than 35 passages and were successfully differentiated into derivatives of all three embryonic germ layers both in vitro and in teratomas.

Until recently, there had been no studies that systematically compared the physiological and differentiation properties of hiPSCs generated using different reprogramming methods in the treatment of disease. A new study headed by Sang-Hun Lee and Kwang-Soo Kim has now compared the ability of neural precursor cells (NPCs) derived from either protein-based iPS cells or viral-based iPS cells to reverse disease in a rat model of Parkinson disease. Lee found several problems with nerve cells derived from virus-based iPS cells that precluded their use in the Parkinson disease model. However, nerve cells derived from protein-based human iPS cells rescued motor defects when transplanted into the brain of rats modeling Parkinson disease. Their conclusion is that protein-based human iPS cells could support the clinical potential of personalized Cell Therapy.

Specifically they found that NPCs derived by lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes. However, cells derived from retrovirus- and protein-based hiPSCs did not. Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging. In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence.