Thyroid Organoids Made from Stem Cells Treat Thyroid-Deficient Mice


Darrell Kotton and his research team from Beth Deaconess Medical Center, in collaboration with researchers from the Boston University School of Medicine have devised a workable protocol for differentiating Human pluripotent stem cells into functional thyroid gland cells.

Every year, many people are diagnosed with an underactive thyroid and many others lose their thyroid as a result of thyroid cancer. Designing treatments that can help replace lost thyroid tissue would certainly be a welcome thing for these patients.

By working with mouse embryonic stem cells, Kotton and his colleagues showed that two growth factors, BMP4 and FGF2, and induce foregut endodermal cells to differentiate into thyroid cells. This simple signaling pathway not only efficiently generates thyroid tissue from endoderm, but this pathway turns out to be commonly used in species as diverse as frogs, mice and humans.

The BMP4/FGF2-treated foregut cells differentiated into small thyroid organics that Kotton and his team were able to transplant into thyroid-deficient mice. These transplantations restored normal thyroid function to these mice.

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While mice cells are a fine model system for human diseases, they are not exactly the same. Can this procedure work with human cells? To answer that question, Kotton and his coworkers used human induced pluripotent stem cells (iPSCs) and subjected them to the same BMP4/FGF2 protocol after they had first differentiated the cells into endoderm. In addition, Kotton and his team made thyroid cells from iPSCs derived from cells taken from patients with a specific type of hypothyroidism (interactive thyroid). These patients lack a gene called NKX2-1, and suffer from congenital hypothyroidism.

The thyroid is responsible for your basal metabolic rate. Hypothyroidism or an interactive thyroid can cause patients to gain weight, feel tired constantly, have trouble concentrating, and have a slow heart rate. Hypothyroidism is usually treated with synthetic thyroid hormones that are taken orally. However, restoring a patient’s own thyroid tissue or even replacing defective thyroid tissue with repaired thyroid tissue would be a huge boon to thyroid patients.

This work has discovered the regulatory mechanisms that drive the establishment of the thyroid. It also provides a significant step toward cell-based regenerative therapy for hypothyroidism and the replacement of the thyroid after thyroid cancer treatments.

These results were published in the journal Cell Stem Cell, October 2015 DOI:10.1016/j.stem.2015.09.004.

Induced Pluripotent Stem Cells Make Lungs


Since my father died of disseminated lung cancer (squamous cell carcinoma), this report has particular meaning to me.

When a person dies, their lungs can be harvested and stripped of their cells. This leaves a so-called “lung scaffold” that can then be used to build new lungs by means of tissue engineering techniques. Lung scaffolds consist of a protein called collagen, and sugar-rich proteins called “proteoglycans” (say that fast five times) and a rubber band-like protein called elastin. Depending on how the lung scaffolds are made more or less of these components can remain in the lung scaffold (see TH Peterson, and others, Cells Tissues Organs. Feb 2012; 195(3): 222–231). The important thing is that the cells are gone and this greatly reduces the tendency for the lung scaffold to be rejected by someone else’s immune system.

Once a lung scaffold is generated from a whole lung, cells can be used to reconstitute the lung. The key is to use the right cell type or mix of cell types and to induce them to form mature lung tissue.

The laboratory of Harald Ott at Harvard University Medical School used a technique called “perfusion decellularization” to make lung scaffolds from the lungs of cadavers. Then he and his co-workers used lung progenitor cells that were derived from induced pluripotent stem cells (iPSCs). This study was published in The Annals of Thoracic Surgery, and it examined the ability of iPSCs to regenerate a functional pulmonary organ

Whole lungs from rat and human cadavers were stripped of their living material by means of constant-pressure perfusion with a strong detergent called sodium dodecyl sulfate (SDS; 0.1% if anyone is interested). Ott and his crew then sectioned some of the resulting lung scaffolds and left others intact, and then applied human iPSCs that had been differentiated into developing lung tissue.

Lung tissue develops from the front part of the developing gut. This tissue is called “endoderm,” since it is in the very innermost layer of the embryo.

Lung Development

Therefore, the iPSCs were differentiated into endoderm with a cocktail of growth factors (FGF, Wnt, Retinoic acid), and then further differentiated in the anterior endoderm (foregut; treated cells with Activin-A, followed by transforming growth factor-β inhibition), and then even further differentiated into anterior, ventral endoderm, which is the precise tissue from which lungs form. In order to be sure that this tissue is lung tissue, they must express a gene called NK2 homeobox 1 (Nkx2.1). If these cells express this gene, then they are certainly lung cells.

Ott and his group showed that their differentiate iPSCs strongly expressed Nkx2.1, and then seeded them on slices and whole lung scaffolds. Then Otts’s group maintained these tissues in a culture system that was meant to mimic physiological conditions.

Those cells cultured on decellularized lung slices divided robustly and committed to the lung lineage after 5 days. Within whole-lung scaffolds and under the physiological mimicking culture, cells upgraded their expression of Nkx2.1. When the culture-grown rat lungs were transplanted into rats, they were perfused and ventilated by host vasculature and airways.

Thus these decellularized lung scaffolds supports the culture and lineage commitment of human iPSC-derived lung progenitor cells. Furthermore, whole-organ scaffolds and a culture system that mimics physiological conditions, allows scientists to enable seeding a combination of iPSC-derived endothelial and epithelial progenitors and enhance early lung fate. Transplantation of these laboratory-grown lungs seem to further maturation of these grafted lung tissues.

Human Stem Cells Converted into Functional Lung Cells


Scientists from the Columbia University Medical Center have succeeded in transforming human stem cells into functional lung and airway cells. This finding has significant potential for modeling lung disease, screening lung-specific drugs, and, hopefully, generating lung tissue for transplantation.

Study leader, Hans-Willem Snoeck, professor of medicine and affiliated with the Columbia Center for Translational Immunology and the Columbia Stem Cell Initiative, said, “Researchers have had relative success in turning human stem cells into heart cells, pancreatic beta cells, intestinal cells, liver cells, and nerve cells, raising all sorts of possibilities for regenerative medicine. Now, we are finally able to make lung and airway cells. This is important because lung transplants have a particularly poor prognosis. Although any clinical application is still many years away, we can begin thinking about making autologous lung transplants – that is, transplants that use a patient’s own skin cells to generate functional lung tissue.”

The research builds on Snoeck’s earlier discoveries in 2011 that a set of chemical factors could induce the differentiation of embryonic or induced pluripotent stem cells into “anterior foregut endoderm,” which is the embryo in the tissue from which the lungs form (Green MD, et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat Biotechnol. 2011 Mar;29(3):267-72).

Human Embryological Development - one month

In his new study, Snoeck and his colleagues found new factors that can transform anterior foregut endoderm cells into lung and airway cells. In particular, Snoeck and his co-workers were able to establish the presence of “type 2 alveolar epithelial cells,” which secrete the lung surfactant that maintains the lung alveoli (those tiny sacs in the lung where all the oxygen exchange takes place).

lung alveolus

With these techniques, lung researchers hope to study diseases like idiopathic pulmonary fibrosis (IPF), in which type 2 epithelial cells seem to divide and produce scarring in the lungs.

“No one knows what causes the disease, and there’s no way to treat it,” said Snoeck. “Using this technology, researchers will finally be able to create laboratory models of IPF, study the disease at the molecular level, and screen drugs for possible treatments or cures. In the longer term, we hope to use this technology to make an autologous lung graft. This would entail taking a lung from a donor, removing all the lung cells, leaving only the lung scaffold; and seeding the scaffold with new lung cells derived from the patient. In this way, rejection problems could be avoided.”

Snoeck is investigating this approach in collaboration with researchers in the Columbia University Department of Biomedical Engineering.