The Promise of Stem Cell Regenerative Therapy for Restoring Thyroid Function

By Jinyoung Choi, PhD and Anthony N. Hollenberg, MD

The clinical features of a severely underactive thyroid (hypothyroidism), known in medical circles as “myxedema,” were first recognized in the 1600s. However, not until 1883, when Swiss physician and surgeon Dr. Theodor Kocher observed myxedema after thyroidectomy (surgical removal of the thyroid), was the link to a properly functioning thyroid gland and its importance established, a discovery that later earned Dr. Kocher the 1909 Nobel Prize in Medicine.

The emergence of modern endocrinology followed in 1891 when British physician Dr. George Redmayne Murray introduced the successful treatment of a myxedema patient with injected extracts of sheep thyroid gland, one of the first examples of hormone replacement therapy. Just one year later, the treatment was made even easier for patients by simply eating, instead of injecting, ground or fried sheep thyroid or tablets of dried thyroid tissue.

More discoveries followed. The thyroid hormone thyroxine (T4) was discovered in 1914. In 1920, the role of iodine in the treatment of goiter (thyroid enlargement) and in cases of severe deficiency to treat an underactive thyroid was established, underscoring the need for dietary iodine supplementation. The structure of T4 was identified and synthesized in 1926. A second and more potent thyroid hormone, triiodothyronine (T3), was discovered and synthesized in 1952. Methods for measuring thyroid stimulating hormone (TSH), the key test for checking whether the thyroid is working properly or the proper amount of thyroid hormone is being taken in by the body, were developed in the 1960s. In 1970, physicians learned that most T3 was produced by the conversion of T4 into T3 outside of the thyroid. This served as the scientific basis for treating hypothyroidism with T4 alone, the mainstay of treatment to this day.

By the mid-1970s congenital hypothyroidism screening programs were implemented, virtually eliminating congenital hypothyroidism in developed portions of the world. Since then, more sophisticated laboratory tests called serum assays have enabled us to diagnosis mild or early hypothyroidism, termed “subclinical hypothyroidism.” Plus, reliable thyroid hormone preparations have enabled physicians to precisely and safely treat hypothyroidism, whatever its degree.

After a century of clinical milestones and triumphs in thyroidology, the field of studying the thyroid and treating those with thyroid conditions, the identification and treatment of hypothyroidism has come a long way. As disease states go, the progression is nothing short of remarkable.

Thanks to advances in science, we are now entering a new phase of exciting major discoveries and breakthroughs that offer the promise of further revolutionizing the treatment of hypothyroidism for many patients.

Our laboratory is pursuing this goal, using regenerative therapy techniques to develop a process for replacing missing or malfunctioning thyroid tissue. This article will explain what regenerative therapy is, discuss some of the progress we have made to date, and how our discoveries could help patients with hypothyroidism.

What is regenerative medicine and therapy?

Regenerative medicine is a research field which deals with the "process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function.” Its focus is to either have the body repair damaged tissues and organs on its own or to grow tissues and organs from the patient’s tissues or organs in the laboratory, then implant them in the body they were taken from. Regeneration could, in some instances, take the place of transplantation, eliminating the obstacles of getting a matching donor and being on powerful medications to prevent organ transplant rejection. For those with hypothyroidism, thyroid gland regeneration would eliminate the need to take lifelong thyroid hormone.

Can’t the thyroid gland regenerate itself just like the liver does?

A normal liver is uniquely able to regenerate itself and to produce the right amount of tissue to make up for what is lost, for example, after donating some tissue for a transplant recipient. Although the thyroid can sometimes make up for loss of function following partial surgical removal, or recover from inflammation, it requires enough remaining normal thyroid tissue to do so. Those with congenital hypothyroidism (born with an absent or underactive thyroid), whose thyroid glands have been surgically removed, or have an underactive thyroid due to chronic inflammation (Hashimoto’s thyroiditis), the most common cause of hypothyroidism in North America, there isn’t enough normal tissue to restore normal function.

Why are regenerative medicine scientists interested in the thyroid gland? Isn’t hypothyroidism generally well treated by taking one pill once a day?

We still don’t know why some patients who are treated with thyroid hormone do not feel as well as they did prior to the time that their thyroid glands became underactive or were removed. And although thyroid hormone treatment is generally straightforward, it requires lifelong adherence to taking medicine on a consistent basis, is affected by a host of medications and illnesses, and needs to be adjusted as we grow up and age, gain or lose significant amounts of weight, and during pregnancy. Regenerating a normal thyroid would provide thyroid hormone levels throughout the day that are indistinguishable from normal thyroid hormones and would enable one’s own body to make the necessary adjustments as thyroid hormone requirements go up and down. Another potential benefit of regenerating thyroid tissue is to enable us to study other thyroid conditions such as thyroid cancer, which could lead to better therapies

What are the key factors for regenerating the thyroid gland?

Stem cells are the key to regenerating tissues. They are immature cells that still have the ability to develop into many different cell types in the body.

There are several types, or classes, of stem cells. Some that are taken from adults fall into the category of “multipotent” (as in multiple or many) stem cells. They can give rise to a small number of cell types. Others such as embryonic stem cells (ESC), which fall into the category of “pluripotent” stem cells, can give rise to any type of cell in the body. The development of a type of pluripotent cell known as induced pluripotent cell (iPC), through reprogramming of adult cells, has been a major breakthrough, because any individual rather than embryos only could be used as a source.

What has been accomplished thus far?

Advances in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology have improved our understanding of follicular cell development and have opened up the possibility of regenerative therapy for hypothyroidism. Follicular cells are the thyroid cells that make thyroid hormone (T4 and T3). Through a series of recent scientific advances made in our laboratories and elsewhere, we have been able to produce follicular cells from the ESC of mice that not only had the ability to grow but, most importantly, were also able to start making thyroid hormone within two weeks and produce normal amounts of thyroid hormone eight weeks after they were transplanted into mice that did not have thyroid glands. Furthermore, the transplanted cells grew normally without any signs of tumor formation.

What remains to be done?

While we are encouraged by what we have accomplished todate in mice and have shown that human iPSCs can be made to function in many key ways like normal human thyroid follicular cells, we need to show that what we have done with mice can be done with human cells. Given the progress in the field to date, we believe that this is possible and transplantable follicles (units made up of thyroid follicular cells) will be produced in the not-too-distant future. Reaching this milestone will enable us to determine whether the approach we developed could be used to repair hypothyroidism in our patients.

To read more about thyroid stem cell regenerative therapy, visit the following: