Derivation of Parathyroid Gland Cells and Their Progenitors from Induced Pluripotent Stem Cells (iPSCs) for Personalized Therapy
Abstract
Hypoparathyroidism occurs when parathyroid gland (PTG) function is compromised or lost through injury, surgery, or radiation therapy or as a result of disease (genetic or autoimmune). Because the PTG regulates calcium metabolism throughout the body, a disruption in its function can be particularly devastating to numerous organs and tissues. Due to the multi-organ pathology of hypoparathyroidism and the limitations of the present pharmacological therapies, it would be beneficial for patients to have a cellular therapy that could mimic the native PTG responses to calcium fluctuations in their blood and compensate for lost PTG function. The recent advance in the development of induced pluripotent stem cells (iPSCs) have created a new opportunity to develop cellular therapies to repair tissues damaged by injury, therapeutic intervention, or disease. These iPSCs can be generated from a patient s somatic cells by reprogramming them to take on the pluripotent features of embryonic cells in that they can be directed to become any cell within the body. Thus, the iPSCs will be directed to differentiate into parathyroid progenitors, and since they are patient-derived, they will be a personalized cellular therapy that bypasses immune system rejection. This is an innovative approach to restore parathyroid function because it bypasses the need for drug supplementation and does not depend on rescuing pieces parathyroid glands for transplantation after a surgery. The directed differentiation of iPSCs into parathyroid progenitors and mature PTG cells will rely on exposure to conditions that mimic, to a degree, the development of the PTG in the embryo. The iPSCs will also be modified so that it will be possible to monitor the expression of genes that are specific to or associated with the PTG by inserting a green fluorescent protein (GFP) reporter gene into the sequences that regulate the expression of genes involved in differentiation of iPSCs into parathyroid progenitors and mature PTG cells. The studies will test the hypothesis whether the differentiated cells will have characteristics consistent with parathyroid cell function, in an ex vivo biological matrix and a mouse model of hypoparathyroidism. Functional efficacy and reversal of hypoparathyroidism in the mouse will be critical to helping define the parameters for the generation and selection of the parathyroid progenitors for transplantation. This proposal will lay the groundwork for developing a patient-specific cell-based therapy for hypoparathyroidism and provide the preliminary information to support a more in-depth proposal that could lead to clinical trials in the future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510261
Entities
People
- Dieter Gruenert
Organizations
- United States Army
- University of California, San Francisco