Thyroid regeneration: how stem cells play a role?

Abstract

Many tissues if not all are thought to contain stem cells that are responsible for regeneration and repair of the tissue after injury. Dysregulation of tissue regeneration may result in various pathological conditions, among which cancer is the most extensively studied. Notably, the so-called cancer stem cells or tumor-initiating cells, have been studied in order to understand the mechanisms of carcinogenesis and/or metastasis. However, the nature of cancer stem cells, let alone normal stem/progenitor cells, particularly those of the thyroid remains elusive. There remains a gap in knowledge between adult thyroid stem/progenitor cells and cancer stem cells of the thyroid, and if and/or how they are related to each other. Understanding of the mechanism for thyroid regeneration and mode of participation of normal adult thyroid stem/progenitor cells in this process will hopefully yield a more complete understanding of the nature of thyroid cancer stem cells, and/or help understand the pathogenesis of other thyroid diseases. This review summarizes the current understanding of adult thyroid stem/progenitor cells, with particular emphasis on how they contribute to thyroid regeneration.

Keywords: OCT4 expression; adult-resident thyroid stem/progenitor cells; partial thyroidectomy; side population; solid cell nest; sphere/spheroid culture; ultimobranchial body cyst.

Figure 1

Appearance of clear cells 2 weeks after partial thyroidectomy. (A) Immunohistochemistry for BrdU (brown color) counterstained with light H&E. Many clear cells are positive for BrdU as representatives shown by red arrows. (B) Immunohistochemistry for Foxa2 (brown color), counterstained with hematoxylin. Clear cells expressing Foxa2 are indicated by arrows.

Figure 2

Co-immunofluorescence for SCA1, BrdU, NKX2-1, and β-gal expression determined at day 7 (A), day 35 (B), and day 120 (C) post-partial thyroidectomy. Colors used were red (SCA1), green (BrdU), white (NXK2-1), and purple (β-gal). At day 7, red and green co-stained positive cells [SCA1(+); BrdU(+)] were found in non-follicular mesenchymal area. At day 35, red/green positive signal was found as an intrafollicular cell, that did not express NKX2-1 (white), nor β-gal (purple). At day 120, intrafollicular cells expressing all four proteins were seen. Double or quadruple positive cell in each panel is shown by an arrow. In (C), strong SCA1 signal is due to cilia that this SCA1(+) cell has.

Figure 3

p63 expression in UBB and SCN of thyroid. (A–C) Immunofluorescence of E13.5 UBB of wild-type mouse embryos for NKX2-1 (A) and p63 immunohistochemistry (B), and merged image (C). Majority of cells express NKX2-1 while a few cells express p63, both being without overlap. (D,E) SCN from E18.5 Nkx2-1-null embryos for H&E (D) and p63 immunohistochemistry (E). p63 is expressed in the stem/basal cell patterns. (F,G) SCN from E18.5 Nkx2-1; p63-double null embryos for H&E (F) and p63 immunohistochemistry (G). Note that the monolayer of p63-negative cells remain in SCN from Nkx2-1; p63-double null embryos. Arrows indicate ciliated cells observed in the cystic structure.

Figure 4

Two models for thyroid regeneration in mice. Model I may be operable when the damage to the thyroid is modest such as when a small portion of thyroid (tissues below the line) is removed. This model may take 2–4 weeks to start producing functionally matured thyrocytes, and may involve immature cells in SCN. SCA1-expressing cells and SCN-like immature cells are shown in red and in pale color, respectively. Ciliated cells are also shown within the immature cells. Model II may become functional when the thyroid damage is massive such as semi-total partial thyroidectomy (a whole lobe and the other lobe below the line as indicated are removed). In this case, follicular cells and C cells are reset to become clear immature cells (shown in light yellow) to start the maturation process again. This model may take 1–2 weeks to start producing functionally mature thyrocytes. Both models can operate simultaneously. PTx, partial thyroidectomy.