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

Stem cells and development Pub Date : 2023-11-01 DOI:10.1089/scd.2023.29015.editorial

Sabrina Corbetta

{"title":"Induced Pluripotent Stem-Derived Parathyroid Cells: An Opportunity for Human Parathyroid Disorders","authors":"Sabrina Corbetta","doi":"10.1089/scd.2023.29015.editorial","DOIUrl":null,"url":null,"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. Matikainen N, T Pekkarinen , EM Ryhänen , and C Schalin-Jäntti . (2021). Physiology of calcium homeostasis: an overview. Endocrinol Metab Clin North Am 50:575–590. Crossref, Medline, Google Scholar2. Mingione A, C Verdelli , A Terranegra , L Soldati , and S Corbetta . (2015). Molecular and clinical aspects of the target therapy with the calcimimetic cinacalcet in the treatment of parathyroid tumors. Curr Cancer Drug Targets 15:563–574. Crossref, Medline, Google Scholar3. Kameda Y. (2023). Cellular and molecular mechanisms of the organogenesis and development, and function of the mammalian parathyroid gland. Cell Tissue Res 393:425–442. Crossref, Medline, Google Scholar4. Yamada T, N Tatsumi , A Anraku , H Suzuki , S Kamejima , T Uchiyama , I Ohkido , T Yokoo , and M Okabe . (2019). Gcm2 regulates the maintenance of parathyroid cells in adult mice. PLoS ONE 14(1):e0210662. Crossref, Medline, Google Scholar5. Verdelli C, A Morotti , GS Tavanti , R Silipigni , S Guerneri , S Ferrero , L Vicentini , V Vaira , and S Corbetta . (2021). The core stem genes SOX2, POU5F1/OCT4, and NANOG are expressed in human parathyroid tumors and modulated by MEN1, YAP1, and β-catenin pathways activation. Biomedicines 9:637. Crossref, Medline, Google Scholar6. Corbetta S, M Belicchi , F Pisati , M Meregalli , C Eller-Vainicher , L Vicentini , P Beck-Peccoz , A Spada , and Y Torrente . (2009). Expression of parathyroid-specific genes in vascular endothelial progenitors of normal and tumoral parathyroid glands. Am J Pathol 175:1200–1207. Crossref, Medline, Google Scholar7. Fang SH, JA Guidroz , Y O'Malley , G Lal , SL Sugg , JR Howe , CS Jensen , and RJ Weigel . (2010). Expansion of a cell population expressing stem cell markers in parathyroid glands from patients with hyperparathyroidism. Ann Surg 251:107–113. Crossref, Medline, Google Scholar8. Vaira V, F Elli , I Forno , V Guarnieri , C Verdelli , S Ferrero , A Scillitani , L Vicentini , F Cetani , et al. (2012). The microRNA cluster C19MC is deregulated in parathyroid tumours. J Mol Endocrinol 49:115–124. Crossref, Medline, Google Scholar9. Verdelli C, L Avagliano , V Guarnieri , F Cetani , S Ferrero , L Vicentini , E Beretta , A Scillitani , P Creo , et al. (2017). Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors. Lab Invest 97:1488–1499. Crossref, Medline, Google Scholar10. Canaff L, V Guarnieri , Y Kim , BYL Wong , A Nolin-Lapalme , DEC Cole , S Minisola , C Eller-Vainicher , F Cetani , et al. (2022). Novel glial cells missing-2 (GCM2) variants in parathyroid disorders. Eur J Endocrinol 186:351–366. Crossref, Medline, Google Scholar11. Vincze S, NV Peters , CL Kuo , TC Brown , R Korah , TD Murtha , J Bellizzi , A Riccardi , K Parham , et al. (2022). GCM2 variants in familial and multiglandular primary hyperparathyroidism. J Clin Endocrinol Metab 107:e2021–e2026. Crossref, Medline, Google Scholar12. Noltes ME, LHJ Sondorp , L Kracht , IF Antunes , R Wardenaar , W Kelder , A Kemper , W Szymanski , WT Zandee , et al. (2022). Patient-derived parathyroid organoids as a tracer and drug-screening application model. Stem Cell Rep 17:2518–2530. Crossref, Medline, Google Scholar13. Bingham EL, SP Cheng , KM Woods Ignatoski , and GM Doherty . (2009). Differentiation of human embryonic stem cells to a parathyroid-like phenotype. Stem Cells Dev 18:1071–1080. Link, Google Scholar14. Woods Ignatoski KM, EL Bingham , LK Frome , and GM Doherty . (2010). Differentiation of precursors into parathyroid-like cells for treatment of hypoparathyroidism. Surgery 148:1186–1189. Crossref, Medline, Google Scholar15. Lawton BR, C Martineau , JA Sosa , S Roman , CE Gibson , MA Levine , and DS Krause . (2020). Differentiation of PTH-expressing cells from human pluripotent stem cells. Endocrinology 161:bqaa141. Crossref, Medline, Google Scholar16. Kano M, N Mizuno , H Sato , T Kimura , R Hirochika , Y Iwasaki , N Inoshita , H Nagano , M Kasai , et al. (2023). Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation. Proc Natl Acad Sci U S A 120:e2216564120. Crossref, Medline, Google Scholar17. Kim JY, S Park , SY Oh , YH Nam , YM Choi , Y Choi , HY Kim , SY Jung , HS Kim , I Jo , and SC Jung . (2022). Density-dependent differentiation of tonsil-derived mesenchymal stem cells into parathyroid-hormone-releasing cells. Int J Mol Sci 23:715. 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","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":"45 6","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stem cells and development","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1089/scd.2023.29015.editorial","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

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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. Matikainen N, T Pekkarinen , EM Ryhänen , and C Schalin-Jäntti . (2021). Physiology of calcium homeostasis: an overview. Endocrinol Metab Clin North Am 50:575–590. Crossref, Medline, Google Scholar2. Mingione A, C Verdelli , A Terranegra , L Soldati , and S Corbetta . (2015). Molecular and clinical aspects of the target therapy with the calcimimetic cinacalcet in the treatment of parathyroid tumors. Curr Cancer Drug Targets 15:563–574. Crossref, Medline, Google Scholar3. Kameda Y. (2023). Cellular and molecular mechanisms of the organogenesis and development, and function of the mammalian parathyroid gland. Cell Tissue Res 393:425–442. Crossref, Medline, Google Scholar4. Yamada T, N Tatsumi , A Anraku , H Suzuki , S Kamejima , T Uchiyama , I Ohkido , T Yokoo , and M Okabe . (2019). Gcm2 regulates the maintenance of parathyroid cells in adult mice. PLoS ONE 14(1):e0210662. Crossref, Medline, Google Scholar5. Verdelli C, A Morotti , GS Tavanti , R Silipigni , S Guerneri , S Ferrero , L Vicentini , V Vaira , and S Corbetta . (2021). The core stem genes SOX2, POU5F1/OCT4, and NANOG are expressed in human parathyroid tumors and modulated by MEN1, YAP1, and β-catenin pathways activation. Biomedicines 9:637. Crossref, Medline, Google Scholar6. Corbetta S, M Belicchi , F Pisati , M Meregalli , C Eller-Vainicher , L Vicentini , P Beck-Peccoz , A Spada , and Y Torrente . (2009). Expression of parathyroid-specific genes in vascular endothelial progenitors of normal and tumoral parathyroid glands. Am J Pathol 175:1200–1207. Crossref, Medline, Google Scholar7. Fang SH, JA Guidroz , Y O'Malley , G Lal , SL Sugg , JR Howe , CS Jensen , and RJ Weigel . (2010). Expansion of a cell population expressing stem cell markers in parathyroid glands from patients with hyperparathyroidism. Ann Surg 251:107–113. Crossref, Medline, Google Scholar8. Vaira V, F Elli , I Forno , V Guarnieri , C Verdelli , S Ferrero , A Scillitani , L Vicentini , F Cetani , et al. (2012). The microRNA cluster C19MC is deregulated in parathyroid tumours. J Mol Endocrinol 49:115–124. Crossref, Medline, Google Scholar9. Verdelli C, L Avagliano , V Guarnieri , F Cetani , S Ferrero , L Vicentini , E Beretta , A Scillitani , P Creo , et al. (2017). Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors. Lab Invest 97:1488–1499. Crossref, Medline, Google Scholar10. Canaff L, V Guarnieri , Y Kim , BYL Wong , A Nolin-Lapalme , DEC Cole , S Minisola , C Eller-Vainicher , F Cetani , et al. (2022). Novel glial cells missing-2 (GCM2) variants in parathyroid disorders. Eur J Endocrinol 186:351–366. Crossref, Medline, Google Scholar11. Vincze S, NV Peters , CL Kuo , TC Brown , R Korah , TD Murtha , J Bellizzi , A Riccardi , K Parham , et al. (2022). GCM2 variants in familial and multiglandular primary hyperparathyroidism. J Clin Endocrinol Metab 107:e2021–e2026. Crossref, Medline, Google Scholar12. Noltes ME, LHJ Sondorp , L Kracht , IF Antunes , R Wardenaar , W Kelder , A Kemper , W Szymanski , WT Zandee , et al. (2022). Patient-derived parathyroid organoids as a tracer and drug-screening application model. Stem Cell Rep 17:2518–2530. Crossref, Medline, Google Scholar13. Bingham EL, SP Cheng , KM Woods Ignatoski , and GM Doherty . (2009). Differentiation of human embryonic stem cells to a parathyroid-like phenotype. Stem Cells Dev 18:1071–1080. Link, Google Scholar14. Woods Ignatoski KM, EL Bingham , LK Frome , and GM Doherty . (2010). Differentiation of precursors into parathyroid-like cells for treatment of hypoparathyroidism. Surgery 148:1186–1189. Crossref, Medline, Google Scholar15. Lawton BR, C Martineau , JA Sosa , S Roman , CE Gibson , MA Levine , and DS Krause . (2020). Differentiation of PTH-expressing cells from human pluripotent stem cells. Endocrinology 161:bqaa141. Crossref, Medline, Google Scholar16. Kano M, N Mizuno , H Sato , T Kimura , R Hirochika , Y Iwasaki , N Inoshita , H Nagano , M Kasai , et al. (2023). Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation. Proc Natl Acad Sci U S A 120:e2216564120. Crossref, Medline, Google Scholar17. Kim JY, S Park , SY Oh , YH Nam , YM Choi , Y Choi , HY Kim , SY Jung , HS Kim , I Jo , and SC Jung . (2022). Density-dependent differentiation of tonsil-derived mesenchymal stem cells into parathyroid-hormone-releasing cells. Int J Mol Sci 23:715. 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

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诱导多能干细胞衍生的甲状旁腺细胞:人类甲状旁腺疾病的机会

干细胞与发育卷。免费获取诱导多能干细胞衍生的甲状旁腺细胞:人类甲状旁腺疾病的机会地址通信:Sabrina Corbetta, MD, PhD，骨代谢紊乱和糖尿病组，IRCCS研究所意大利，Via L. Ariosto, Milan, 20145，意大利电子邮件地址:[email protected]https://orcid.org/0000-0001-8140-3175Bone代谢紊乱和糖尿病组，IRCCS研究所，意大利米兰。米兰大学生物医学、外科和牙科科学系，意大利米兰。搜索本文作者的更多论文发表在线:2023年11月3日https://doi.org/10.1089/scd.2023.29015.editorialAboutSectionsPDF/EPUB权限和引文missionsdownload引文strack引文添加到收藏返回发表分享分享上facebook推特链接InRedditEmail甲状旁腺参与磷酸钙稳态。由钙和磷酸盐形成的羟基磷灰石晶体是骨骼骨基质的主要无机成分。钙是神经肌肉兴奋性、肌肉收缩和凝血所必需的，而磷酸盐是能量分子三磷酸腺苷的基础。甲状旁腺细胞感知细胞外钙浓度并释放甲状旁腺激素(PTH)，它通过作用于骨和肾产生高钙效应。甲状旁腺激素诱导的骨基质吸收增加循环钙和磷酸盐水平。甲状旁腺素诱导超滤尿液和肾腰部的钙重吸收;高磷血症诱导其分泌，以避免软组织中磷酸钙沉淀[1]。甲状旁腺细胞的特异性钙感应活性是由钙感应受体(CASR)的分子结构介导的，CASR是一种g蛋白偶联的七个跨膜结构域受体[2]。TBX1基因敲除小鼠的研究表明，甲状旁腺细胞在胚胎发育过程中起源于内胚层细胞，与间充质细胞相互作用[3]。胚胎发生时，第三和第四咽袋细胞中甲状旁腺主调控基因GCM2的表达驱动向甲状旁腺细胞分化[3]。成年期GCM2也可能在甲状旁腺细胞增殖和维持中发挥作用[4]，维持CASR和PTH基因的表达。甲状旁腺疾病的特点是由于钙敏感性和/或甲状旁腺激素释放的改变而导致循环钙和磷酸盐的失调。临床甲状旁腺疾病的特点是甲状旁腺功能低下伴低钙血症和甲状旁腺功能亢进伴高钙血症。甲状旁腺功能减退症是由于甲状旁腺功能细胞的丧失，最常见的是术后甲状旁腺功能减退症(继发于甲状腺、甲状旁腺、喉、颈淋巴清扫)和常规照射后的终身状态。罕见的是，它是由遗传和自身免疫性(检查点抑制剂诱导)甲状旁腺功能低下和假性甲状旁腺功能低下(鸟嘌呤核苷酸结合蛋白G(S)亚单位α相关疾病1型和2型)维持的。从临床角度来看，甲状旁腺功能低下患者会经历肌肉痉挛和疼痛、感觉异常、抽搐或由基底节区钙化、白内障、心律失常和充血性心力衰竭引起的锥体外综合征。原发性甲状旁腺功能亢进(PHPT)是由甲状旁腺瘤形成的，95%的病例为良性肿瘤。临床上，大多数轻度PHPT患者伴有骨质疏松和/或脆性骨折和肾脏受累(肾结石和肾功能丧失)。甲状旁腺肿瘤的发生已部分探讨;尽管如此，值得注意的是，多能干细胞的参与已经提出。干细胞和胚胎细胞标记物，如核心干细胞基因SOX2、OCT4和NANOG[5]，造血祖细胞标记物CD34[6]，间充质干细胞标记物CD44 [7]， microRNA簇C19MC[8]，甲状旁腺胚胎基因TBX1[9]和GCM2[10,11]在甲状旁腺肿瘤细胞中表达和失调。此外，在人类甲状旁腺增生衍生的类器官中也发现了具有自我更新功能的甲状旁腺细胞[12]。除甲状旁腺疾病外，甲状旁腺细胞功能对骨骼骨骼健康至关重要，模拟骨合成代谢甲状旁腺作用的抗骨质疏松药物teriparatide和abaloparatide已被开发出来，目前用于临床治疗骨质疏松患者，有效降低脆性骨折的风险。然而，由于缺乏保存钙敏感性和甲状旁腺分泌的甲状旁腺细胞系，研究甲状旁腺的病理生理是困难的。因此，甲状旁腺肿瘤的发生是部分阐明和靶向治疗缺乏。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Stem cells and development

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