Using microRNAs to control activation status of hepatic stellate cells and to prevent fibrosis in progressive liver diseases
Provided herein are methods and compositions for treatment and/or prevention of liver disease. Aspects of the present disclosure relate to the engineering of a quiescent Hepatic Stellate Cell, and use of the engineered quiescent Hepatic Stellate Cell, or population thereof in the treatment and/or prevention of liver disease.
1. A method of inducing quiescence in a hepatic stellate cell (HSC), the method comprising: contacting an hepatic stellate cell with an effective amount of an exogenous miR-412 or an exogenous nucleic acid sequence encoding miR-412 for a time and under conditions that are sufficient to induce quiescence in the HSC cell.
2. The method of claim 1 , wherein the method further comprises contacting the hepatic stellate cell with an effective amount of miR15a or a nucleic acid encoding miR15a.
3. The method of claim 2 , wherein the hepatic stellate cell is contacted with exogenous miR-412 and miR-15a substantially simultaneously.
4. The method of claim 1 , wherein expression of alpha smooth actin (Acta2) and/or alpha-1 type I collagen (Colla1) protein levels are decreased in the quiescent HSC cell as compared to the protein levels of Acta2 and/or Colla1 in an activated HSC.
5. The method of claim 1 , wherein intracellular lipid droplets of the HSC are increased following the contacting step, thereby indicating the HSC is quiescent.
6. The method of claim 1 , wherein the exogenous nucleic acid sequence encoding miR412 and/or the nucleic acid sequence encoding miR-15a is/are transiently or constitutively expressed in the HSC.
7. The method of claim 1 , wherein the exogenous nucleic acid sequence encoding miR412 and/or the nucleic acid sequence encoding miR-15a is/are comprised by a vector.
8. The method of claim 1 , wherein the HSC is derived from an embryonic stem cell, a pluripotent stem cell, or an induced pluripotent stem cell (iPS cell).
9. A method for treating and/or delaying progression of a liver disease associated with activated HSCs in a subject in need thereof, the method comprising: administering to a subject having or at risk of having the liver disease, a composition comprising a quiescent HSC cell of claim 1 or a population thereof, thereby treating and/or delaying progression the liver disease in the subject.
10. The method of claim 9 , wherein the quiescent HSC cell or population thereof comprises exogenous expression of a nucleic acid sequence encoding miR-412 and/or exogenous expression of a nucleic acid sequence encoding miR-15a.
11. The method of claim 9 , further comprising, prior to administration, a step of diagnosing the subject with liver disease prior to administration of the composition.
12. A composition comprising a quiescent HSC of claim 1 or a population thereof and a pharmaceutically acceptable carrier.
13. The composition of claim 12 , further comprising a scaffold.
14. The composition of claim 12 , wherein the scaffold is biodegradable.