TY - JOUR
T1 - In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts
AU - Banga, Anannya
AU - Akinci, Ersin
AU - Greder, Lucas V.
AU - Dutton, James R.
AU - Slack, Jonathan M W
PY - 2012/9/18
Y1 - 2012/9/18
N2 - In embryonic development, the pancreas and liver share developmental history up to the stage of bud formation. Therefore, we postulated that direct reprogramming of liver to pancreatic cells can occur when suitable transcription factors are overexpressed. Using a polycistronic vector we misexpress Pdx1, Ngn3, and MafA in the livers of NOD-SCID mice rendered diabetic by treatment with streptozotocin (STZ). The diabetes is relieved long term. Many ectopic duct-like structures appear that express a variety of β-cell markers, including dense core granules visible by electron microscopy (EM). Use of a vector also expressing GFP shows that the ducts persist long after the viral gene expression has ceased, indicating that this is a true irreversible cell reprogramming event. We have recovered the insulin+ cells by cell sorting and shown that they display glucose-sensitive insulin secretion. The early formed insulin+ cells can be seen to coexpress SOX9 and are also labeled in mice lineage labeled for Sox9 expression. SOX9+ cells are normally found associated with small bile ducts in the periportal region, indicating that the duct-like structures arise from this source. This work confirms that developmentally related cells can be reprogrammed by suitable transcription factors and also suggests a unique therapy for diabetes.
AB - In embryonic development, the pancreas and liver share developmental history up to the stage of bud formation. Therefore, we postulated that direct reprogramming of liver to pancreatic cells can occur when suitable transcription factors are overexpressed. Using a polycistronic vector we misexpress Pdx1, Ngn3, and MafA in the livers of NOD-SCID mice rendered diabetic by treatment with streptozotocin (STZ). The diabetes is relieved long term. Many ectopic duct-like structures appear that express a variety of β-cell markers, including dense core granules visible by electron microscopy (EM). Use of a vector also expressing GFP shows that the ducts persist long after the viral gene expression has ceased, indicating that this is a true irreversible cell reprogramming event. We have recovered the insulin+ cells by cell sorting and shown that they display glucose-sensitive insulin secretion. The early formed insulin+ cells can be seen to coexpress SOX9 and are also labeled in mice lineage labeled for Sox9 expression. SOX9+ cells are normally found associated with small bile ducts in the periportal region, indicating that the duct-like structures arise from this source. This work confirms that developmentally related cells can be reprogrammed by suitable transcription factors and also suggests a unique therapy for diabetes.
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U2 - 10.1073/pnas.1201701109
DO - 10.1073/pnas.1201701109
M3 - Article
C2 - 22949652
AN - SCOPUS:84866550121
SN - 0027-8424
VL - 109
SP - 15336
EP - 15341
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -