RRC ID 76884
Author Kano M, Mizuno N, Sato H, Kimura T, Hirochika R, Iwasaki Y, Inoshita N, Nagano H, Kasai M, Yamamoto H, Yamaguchi T, Suga H, Masaki H, Mizutani E, Nakauchi H.
Title Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation.
Journal Proc Natl Acad Sci U S A
Abstract Patients with permanent hypoparathyroidism require lifelong replacement therapy to avoid life-threatening complications, The benefits of conventional treatment are limited, however. Transplanting a functional parathyroid gland (PTG) would yield better results. Parathyroid gland cells generated from pluripotent stem cells in vitro to date cannot mimic the physiological responses to extracellular calcium that are essential for calcium homeostasis. We thus hypothesized that blastocyst complementation (BC) could be a better strategy for generating functional PTG cells and compensating loss of parathyroid function. We here describe generation of fully functional PTGs from mouse embryonic stem cells (mESCs) with single-step BC. Using CRISPR-Cas9 knockout of Glial cells missing2 (Gcm2), we efficiently produced aparathyroid embryos for BC. In these embryos, mESCs differentiated into endocrinologically mature PTGs that rescued Gcm2-/- mice from neonatal death. The mESC-derived PTGs responded to extracellular calcium, restoring calcium homeostasis on transplantation into mice surgically rendered hypoparathyroid. We also successfully generated functional interspecies PTGs in Gcm2-/- rat neonates, an accomplishment with potential for future human PTG therapy using xenogeneic animal BC. Our results demonstrate that BC can produce functional endocrine organs and constitute a concept in treatment of hypoparathyroidism.
Volume 120(28)
Pages e2216564120
Published 2023-7-11
DOI 10.1073/pnas.2216564120
PMID 37379351
PMC PMC10334775
MeSH Animals Blastocyst Calcium Calcium, Dietary Humans Hypoparathyroidism* / genetics Hypoparathyroidism* / therapy Mice Parathyroid Glands* Rats
IF 9.412
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384)