Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication

Area of Science:

• Endocrinology
• Cell Biology
• Epigenetics

Background:

• Diabetes mellitus is characterized by the loss of insulin-secreting beta cells.
• Adult beta cells exhibit limited proliferation, posing a challenge for cell transplantation therapies.
• The cell cycle inhibitor p57 regulates beta cell division and its expression is epigenetically controlled.

Purpose of the Study:

• To investigate if targeted demethylation of the imprinting control region 2 (ICR2) can induce beta cell proliferation.
• To assess the efficacy of a transcription activator-like effector protein fused to TET1 (ICR2-TET1) in promoting beta cell expansion.

Main Methods:

• Overexpression of ICR2-TET1 in human fibroblasts and islets.
• Analysis of p57 expression levels and cell proliferation markers (Ki-67).
• Transplantation of epigenetically edited human islets into diabetic immunodeficient mice.

Main Results:

• ICR2-TET1 overexpression reduced p57 levels and increased proliferation in human fibroblasts.
• Human islets with ICR2-TET1 showed repressed p57, upregulated Ki-67, and maintained glucose-sensing function.
• Transplanted epigenetically edited islets demonstrated enhanced beta cell replication in vivo.

Conclusions:

• Epigenetic editing via ICR2-TET1 is a viable strategy to induce beta cell proliferation.
• This method offers a potential solution to the scarcity of transplantable beta cells for diabetes treatment.