In vivo reprogramming with viral vectors
Although multicellular organisms are made up of many cell types, all with essentially identical genomes, cells rarely interconvert between cell types. Once a cell acquires a specific cell fate, it generally does not assume the phenotype of an alternate cell type. However, in certain developmental and repair processes, cells do undergo reprogramming to alternate cell identities, demonstrating that cell type is somewhat plastic1. There is now a concerted effort by many labs to study and manipulate cell type plasticity, and a lot of progress has been made2. Recently, there have been some major breakthroughs in reprogramming, allowing clinically relevant cell types to be generated in animal models in vivo. Here are a couple recent examples, both utilizing viral vectors to trigger reprogramming.
Replacing lost liver cells
In most types of chronic liver disease, the accumulation of fibrosis and associated hepatocyte loss can lead to serious health issues, including organ failure. Slowing or halting the progressive loss of liver tissue is vital to the health of these patients. Recently, Song et al. developed a method for converting fibroblasts already present in the liver into hepatocytes 3. To reprogram cultured fibroblasts into induced hepatocytes (iHep), the researchers used a polycistronic lentiviral vector expressing four transcription factors. Then, using a specially tagged adenoviral vector expressing the same four factors, they successfully generated iHeps in vivo, in a mouse model of chronic liver disease. They even found that induction of iHeps in their mouse model reduced liver fibrosis. This may open new avenues for the treatment of chronic liver disease in humans.
Replenishing neurons in Parkinson’s
Parkinson’s disease is characterized by the progressive loss of dopamine neurons in the midbrain. Currently, there is no effective treatment for this neurodegeneration, and any effective means to replace the lost neurons could be very promising for Parkinson’s patients. Rivetti di Val Cervo et al. have now found a method for converting cultured human astrocytes or in vivo mouse astrocytes into induced dopamine neurons (iDANs)4. Their method utilizes lentiviral vectors to co-express three transcription factors along with a micro-RNA. This resulted in the efficient conversion of astrocytes to iDANs. In an in vivo mouse model of Parkinson’s disease, they observed that the iDANs very closely resembled endogenous dopamine neurons, and were even able to correct Parkinson’s-related movement symptoms in their mouse model. These finding may represent progress toward new, gene-based therapies for neurodegenerative diseases.
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- Jessen KR, Mirsky R, Arthur-Farraj P. The Role of Cell Plasticity in Tissue Repair: Adaptive Cellular Reprogramming. Dev Cell. 2015 Sep 28;34(6):613-20.
- Srivastava D, DeWitt N. In Vivo Cellular Reprogramming: The Next Generation. Cell. 2016 Sep 8;166(6):1386-96.
- Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, Reetz J, Brandes S, Dai Z, Pützer BM, Araúzo-Bravo MJ, Steinemann D, Luedde T, Schwabe RF, Manns MP, Schöler HR, Schambach A, Cantz T, Ott M, Sharma AD. Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell Stem Cell. 2016 Jun 2;18(6):797-808.
- Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng YH, Sánchez SP, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model. Nat Biotechnol. 2017 May;35(5):444-452.
- Ariyachet C, Tovaglieri A, Xiang G, Lu J, Shah MS, Richmond CA, Verbeke C, Melton DA, Stanger BZ, Mooney D, Shivdasani RA, Mahony S, Xia Q, Breault DT, Zhou Q. Reprogrammed Stomach Tissue as a Renewable Source of Functional β Cells for Blood Glucose Regulation. Cell Stem Cell. 2016 Mar 3;18(3):410-21.