Induced Pluripotent Stem-Derived Parathyroid Cells: An Opportunity for Human Parathyroid Disorders

Abstract

Stem Cells and DevelopmentVol. 32, No. 21-22 Guest EditorialFree AccessInduced Pluripotent Stem-Derived Parathyroid Cells: An Opportunity for Human Parathyroid DisordersSabrina CorbettaSabrina CorbettaAddress correspondence to: Sabrina Corbetta, MD, PhD, Bone Metabolism Disorders and Diabetes Unit, IRCCS Istituto Auxologico Italiano, Via L. Ariosto, Milan 20145, Italy E-mail Address: [email protected]https://orcid.org/0000-0001-8140-3175Bone Metabolism Disorders and Diabetes Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy.Department of Biomedical, Surgical and Dentistry Sciences, University of Milan, Milan, Italy.Search for more papers by this authorPublished Online:3 Nov 2023https://doi.org/10.1089/scd.2023.29015.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Parathyroid glands are involved in calcium-phosphate homeostasis. Hydroxyapatite crystals formed by calcium and phosphate are the main inorganic constituents of skeletal bone matrix. Calcium is needed for neuromuscular excitability, muscle contraction, and coagulation, while phosphate is fundamental for the energetic molecule adenosine triphosphate.Parathyroid cells sense extracellular calcium concentrations and release parathormone (PTH), which exerts a hypercalcemic effect by acting on bone and kidney. PTH-induced bone matrix resorption increases circulating calcium and phosphate levels. PTH induces calcium reabsorption from ultrafiltrate urine and phosphate renal waist; its secretion was induced by hyperphosphatemia, to avoid calcium-phosphate precipitation in soft tissues [1]. The specific calcium-sensing activity of the parathyroid cells is mediated by the molecular structure of the calcium-sensing receptor (CASR), a G-protein coupled seven transmembrane domains receptor [2].Parathyroid cells origin from the endoderm cells during the embryonic development interacting with mesenchymal cells as demonstrated by studies in mice knockout for TBX1 gene [3]. The expression of the parathyroid master regulatory gene GCM2 in cells of the third and fourth pharyngeal pouches during embryogenesis drives differentiation toward parathyroid cells [3]. GCM2 may play a role for parathyroid cell proliferation and maintenance also in adulthood [4], sustaining the expression of CASR and PTH genes.Parathyroid diseases are characterized by circulating calcium and phosphate deregulation due to alterations of the calcium sensitivity and/or of PTH release. Clinical parathyroid diseases are characterized by conditions of hypoparathyroidism associated with hypocalcemia and hyperparathyroidism associated with hypercalcemia.Hypoparathyroidism is due to loss of parathyroid functional cells, most frequently consistent in life-long condition of postsurgical hypoparathyroidism (secondary to thyroid, parathyroid, larynx, cervical lymphonodal dissection) and post-conventional irradiation. Rarely, it is sustained by genetic and autoimmune (checkpoint inhibitors-induced) hypoparathyroidism, and pseudohypoparathyroidism (Guanine Nucleotide-Binding Protein G(S) Subunit Alpha-related disorder types 1 and 2). From a clinic point of view, hypoparathyroid patients experience muscle cramps and pain, paresthesia, convulsion, or extrapiramidal syndrome due to basal ganglia calcifications, cataracts, cardiac arrythmia, and congestive heart failure.Primary hyperparathyroidism (PHPT) is sustained by parathyroid neoplasia, which in 95% of cases are benign tumors. Clinically, most patients with mild PHPT are affected with osteoporosis and/or fragility fractures and kidney involvement (kidney stones and loss of kidney function). Parathyroid tumorigenesis has been partially explored; nonetheless, it is of note that pluripotent stem cells involvement has been suggested. Stem and embryonic cell markers, such as the core stem cell genes SOX2, OCT4 and NANOG [5], the hematopoietic progenitor cell markers CD34 [6], the mesenchymal stem cell marker CD44 [7], the microRNA cluster C19MC [8], the parathyroid embryonic genes TBX1 [9], and GCM2 [10,11] are expressed and deregulated in parathyroid tumor cells. Moreover, parathyroid cells displaying self-renewal have been identified in human parathyroid hyperplasia-derived organoid [12].Besides parathyroid diseases, parathyroid cell function is crucial for skeletal bone health and anti-osteoporotic drugs mimicking the bone anabolic parathyroid effects, namely teriparatide and abaloparatide, have been developed and currently used in clinical setting for the treatment of osteoporotic patients, where they efficiently reduce the risk of fragility fractures.However, investigating parathyroid pathophysiology is difficult due to the lack of parathyroid cell lines conserving the calcium sensitivity and PTH secretion. Consequently, parathyroid tumorigenesis is partially elucidated and target therapy are lacking. Similarly, replacement therapy with calcium and calcitriol, the active form of vitamin D, and PTH in hypoparathyroidism is far from optimal and long life safe, and organ transplantation is not indicated.Therefore, there are a number of unmet needs for patients with parathyroid disorders and for patients with bone diseases involving parathyroid deregulation warranting the availability of cell models of human parathyroid cells.In the present SCD issue, Nakatsuka et al. provide evidence that human-induced pluripotent stem (iPS) cells may be an option. First, it should be considered that parathyroid glands generated from human iPS cells must in vivo regulate PTH secretion in response to extracellular calcium concentrations. Thus, parathyroid cells must (1) express CASR, (2) maintain baseline PTH secretion, and (3) if extracellular calcium concentration falls immediately secrete PTH in amounts adequate to restore normocalcemia.Nakatsuka et al. reported a new method of parathyroid cell differentiation from a human iPS cell line, namely the human invariant natural killer T-iPSCs#2 cell line. The differentiated cells expressed PTH and CASR and adopted a cell aggregation similar to the parathyroid gland. In this generated parathyroid cells, as the extracellular calcium concentration increased, PTH and GCM2 expression tended to decrease.Generation of parathyroid-like cells was previously achieved using mouse embryonic stem cells [13], human embryonic stem cells [14,15], mouse iPS cells [16], and human adult mesenchymal stem cells [17]. Similar to what was reported in these previous experimental studies, Nakatsuka et al. established a three-step differentiation resembling parathyroid embryogenesis. First, cells were driven toward anterior foregut endoderm (AFE) differentiation, then differentiation in pharyngeal endoderm (PE) epithelial cells was induced; finally, PTH secretion was stimulated. Previous studies and Nakatsuka et al. tested different protocols for differentiation, though most of them demonstrated the pivotal role of1.Activin A and WNT pathway inhibitors in AFE differentiation; Activin A is a widely used transforming growth factor-β superfamily protein that enables cell differentiation through multiple pathways.2.Sonic Hedgehog inhibitors in PE differentiation.3.Low calcium medium to induce PTH expression and release.Indeed, despite the number of attempts reported here, generation of functional parathyroid glands from human embryonic stem cells or iPS cells for research and clinical use has not hitherto been achieved.In conclusion, the study by Nakatsuka et al., contributes to the following items: 1.Defining the optimal protocol for iPS-derived parathyroid cells and its efficiency.2.Obtaining insight about parathyroid cell embryonic origin.3.Establishing a cell model for investigation of physiology and pathophysiology of human parathyroid glands, providing an option for unmet needs due to lack of immortalized human parathyroid cells, retaining extracellular calcium sensitivity and PTH secretion.4.Providing experimental knowhow for development of replacement cell therapy for PTH deficiency-related disorders.References1. 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Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 32Issue 21-22Nov 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Sabrina Corbetta.Induced Pluripotent Stem-Derived Parathyroid Cells: An Opportunity for Human Parathyroid Disorders.Stem Cells and Development.Nov 2023.667-669.http://doi.org/10.1089/scd.2023.29015.editorialPublished in Volume: 32 Issue 21-22: November 3, 2023PDF download