The potential to use stem cells to regenerate lost or damaged tissue has long been a goal of the medical community. While great strides have been made in recent years, one area that has been slow to yield results is the creation of functional organoids— three-dimensional, miniature structures that resemble in vivo organs. This is due in part to the difficulty in recapitulating the complex microenvironment found within native tissue.
Now, researchers from the Massachusetts General Hospital (MGH) have shown that stem cells can be used to create functional organoids that mimic human parathyroid tissue. In doing so, they provide a proof of concept that could lead to the development of personalized therapeutics for a variety of diseases.
The MGH team took advantage of recent advances in stem cell technology to create what are known as induced pluripotent stem cells (iPSCs). These are derived from adult cells that have been genetically reprogrammed to return to an embryonic state, from which they can then differentiate into any cell type in the body.
Using iPSCs from patients with primary hyperparathyroidism— a condition characterized by the overproduction of parathyroid hormone (PTH) — the team was able to generate three-dimensional organoids that displayed many of the key features of normal parathyroid tissue. Importantly, the organoids produced PTH in response to changes in calcium levels, just as native parathyroid tissue does.
The findings, published in the journal Nature Medicine, demonstrate that stem cell-derived organoids can be used to model human disease and could potentially be used to screen for new drugs or to test the efficacy of existing ones.
The development of personalized organoids also opens up the possibility of using them as cellular therapeutics. In the case of primary hyperparathyroidism, for example, it may one day be possible to transplant patient-derived organoids into the body to replace the dysfunctional tissue and restore normal calcium regulation.
While much work remains to be done, the MGH team’s findings represent an important step forward in the use of stem cells to model and treat human disease.
In a first-of-its-kind study, researchers have generated functional, three-dimensional human organoids from stem cells that mimic the structure and function of the parathyroid gland.
The parathyroid gland is a small endocrine gland that regulates calcium metabolism. It is located in the neck, behind the thyroid gland.
The new organoids, which were generated from induced pluripotent stem cells (iPSCs), were able to produce the hormone parathyroid hormone (PTH) and respond to changes in calcium levels in the blood.
Importantly, when transplanted into mice, the organoids were able to regulate calcium metabolism in the animals, demonstrating their potential to be used as a replacement therapy for patients with parathyroid disorders.
The study, which was published in the journal Nature Cell Biology, was conducted by researchers at the University of California, San Francisco (UCSF).
“Our goal was to generate functional, three-dimensional organoids that recapitulate the structure and function of the human parathyroid gland,” said senior author Matthias Hebrok, PhD, director of the UCSF Diabetes Center.
“We are excited about the potential of these organoids to serve as a personalized therapy for patients with parathyroid disorders.”
The parathyroid gland is composed of four types of cells: chief cells, oxyphil cells, principal cells, and parafollicular cells.
Each cell type has a different function, but all are important for the regulation of calcium metabolism.
The new organoids mimic the structure of the gland, with different cell types arranged in specific layers.
“We were able to show that the different cell types in the organoids are arranged in the same way as they are in the human gland,” said lead author Katie Cadet, PhD, a postdoctoral fellow in the UCSF Diabetes Center.
“This is important because it suggests that the organoids are functional and have the potential to be used as a replacement therapy.”
In addition to demonstrating that the organoids are functional, the researchers also showed that they are responsive to changes in calcium levels in the blood.
“We found that when calcium levels in the blood are low, the organoids increase production of PTH,” said Cadet.
“Conversely, when calcium levels are high, the organoids reduce production of PTH.”
The ability of the organoids to respond to changes in calcium levels is important, as it demonstrates their potential to be used as a replacement therapy for patients with parathyroid disorders.
“Patients with parathyroid disorders often have episodes of high or low calcium levels, which can lead to serious health complications,” said Hebrok.
“The ability of the organoids to respond to changes in calcium levels suggests that they could be used to regulate calcium metabolism in these patients.”
The next step in the research is to test the organoids in larger animals.
“We are currently working on transplanting the organoids into pigs,” said Hebrok.
“If the transplant is successful, it will be an important step towards clinical trials in humans.”
The new study provides proof-of-concept that stem cell-derived organoids can be used to generate functional replacement tissues for the treatment of endocrine disorders.
The findings offer hope for the development of personalized therapies for patients with parathyroid disorders and other endocrine disorders.
