Methods of differentiating stem cells by modulating MIR-124
Inventors
Lee, Jau-Nan • LEE, Tony Tung-Yin • Lee, Yuta
Assignees
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Publication Number
US-11028366-B2
Publication Date
2021-06-08
Expiration Date
Abstract
Provided herein are methods of differentiating stem cells via modulating miR-124, and the differentiated cells thereby. Also provided herein are methods for the treatment of diseases using the differentiated cells.
Core Innovation
The invention relates to increasing insulin production in a human in need thereof by administering an isolated human pancreatic progenitor cell. The isolated human pancreatic progenitor cell expresses insulin and betatrophin, and the insulin production in the human increases in response to glucose stimulation. The disclosed cell-based approach links insulin production to glucose stimulation through the expressed markers in the administered pancreatic progenitor cells.
The disclosed framework connects miR-124 induction to differentiation toward pancreatic progenitors/endoderm and toward insulin-producing, glucose-responsive cells. A spatiotemporal induction of miR-124 is linked to an FGF/bFGF-FGFR1/PI3K/Akt/CREB1 signaling axis, with downstream repression of Smad4/Mixl1 and Cdx2 and reciprocal activation of Oct4. This regulatory cascade is used to drive coordinated expression of pancreatic and beta-cell-associated factors including betatrophin, C-peptide, and insulin.
The disclosed differentiation outcome includes glucose-stimulated insulin/C-peptide release together with expression of pancreatic markers such as Ngn3, Pdx1, Sox17, Foxa2, and Nkx6.1. The document also reports miR-124a 3'UTR-targeted reporter assays and immunostaining and ultrastructure evidence, supporting the described miR-124-linked transcriptional and marker dynamics during differentiation toward insulin-producing cells.
Claims Coverage
The partial content explicitly identifies one independent claim and several dependent claims. Across these claims, the inventive core centers on administering an isolated human pancreatic progenitor cell expressing insulin and betatrophin to increase glucose-stimulated insulin production in a human in need thereof, with dependent claims adding further expressed factors, narrowing the patient population, and specifying delivery by injection.
Administering isolated pancreatic progenitor cell expressing insulin and betatrophin
Administer an isolated human pancreatic progenitor cell to a human in need thereof, wherein the isolated human pancreatic progenitor cell expresses insulin and betatrophin.
Increasing insulin production in response to glucose stimulation
Increase insulin production in the human, wherein the insulin production is increased in response to glucose stimulation in the human.
Progenitor cell expressing C-peptide
The method of claim 1, wherein the isolated human pancreatic progenitor cell further expresses C-peptide.
Progenitor cell expressing Ngn3
The method of claim 1, wherein the isolated human pancreatic progenitor cell further expresses Ngn3.
Progenitor cell expressing C-peptide and Ngn3
The method of claim 1, wherein the isolated human pancreatic progenitor cell expresses C-peptide and Ngn3.
Human in need with diabetes-associated symptoms
The method of claim 1, wherein the human in need has one or more symptoms associated with diabetes.
Administration by injecting
The method of claim 1, wherein the administering comprises injecting the isolated pancreatic progenitor cells to the human.
Collectively, the claims cover a method that administers isolated human pancreatic progenitor cells expressing insulin and betatrophin to increase glucose-stimulated insulin production, with dependent claims further requiring additional expressed markers, narrowing to humans with diabetes-associated symptoms, and specifying injection as a delivery mode.
Stated Advantages
Increased insulin production in the human in response to glucose stimulation.
Documented Applications
Cell-based therapy for diabetes and other diseases using differentiated insulin-producing, glucose-responsive cells.
Drug screening/toxicity assays using the differentiated pancreatic progenitors.
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