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Salivary glands regenerate after radiation injury through SOX2‐mediated secretory cell replacement

Emmerson, Elaine ; May, Alison J ; Berthoin, Lionel ; Cruz‐Pacheco, Noel ; Nathan, Sara ; Mattingly, Aaron J ; Chang, Jolie L ; Ryan, William R ; Tward, Aaron D ; Knox, Sarah M

EMBO molecular medicine, 2018-03, Vol.10 (3), p.n/a [Periódico revisado por pares]

England: EMBO Press

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Título:
Salivary glands regenerate after radiation injury through SOX2‐mediated secretory cell replacement
Autor: Emmerson, Elaine ; May, Alison J ; Berthoin, Lionel ; Cruz‐Pacheco, Noel ; Nathan, Sara ; Mattingly, Aaron J ; Chang, Jolie L ; Ryan, William R ; Tward, Aaron D ; Knox, Sarah M
Assuntos: Acetylcholine - metabolism ; Acetylcholine receptors (muscarinic) ; Acinar cells ; Acinar Cells - metabolism ; Acinar Cells - radiation effects ; Adult ; Aged ; Animals ; Cancer ; Cell Lineage - radiation effects ; Cell Proliferation - radiation effects ; Chorda Tympani Nerve - pathology ; Chorda Tympani Nerve - radiation effects ; Degeneration ; Female ; Genotoxicity ; Glands ; Head & neck cancer ; Homeostasis ; Humans ; Male ; Mice, Inbred C57BL ; Middle Aged ; Neural stem cells ; Parasympathetic nervous system ; Radiation ; Radiation Injuries - metabolism ; Radiation Injuries - pathology ; Radiation Injuries - physiopathology ; Radiation, Ionizing ; radiotherapy ; Receptors, Muscarinic - metabolism ; Regeneration ; Salivary gland ; Salivary Glands - pathology ; Salivary Glands - physiopathology ; Salivary Glands - radiation effects ; Signal Transduction ; SOX2 ; SOXB1 Transcription Factors - metabolism ; Stem cells ; Stem Cells - metabolism ; Stem Cells - radiation effects ; γ Radiation
É parte de: EMBO molecular medicine, 2018-03, Vol.10 (3), p.n/a
Notas: These authors contributed equally to this work as first authors
Descrição: Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co‐morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve‐dependent mechanism. Synopsis Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models. SOX2+ stem cells are essential to acinar cell replacement in the sublingual gland (SLG) during homeostasis and after radiation‐induced damage. SOX2‐mediated acinar cell replacement is contingent on neuronal muscarinic signalling. In the absence of nerves, a muscarinic mimetic can drive SOX2‐mediated regeneration. SOX2 function is essential for SLG regeneration following radiation‐induced injury. SOX2 along with parasympathetic nerves are diminished in human salivary gland biopsies following irradiation therapy and SOX2 and the acinar lineage are upregulated in response to muscarinic activation. Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models.
Editor: England: EMBO Press
Idioma: Inglês

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Salivary glands regenerate after radiation injury through SOX2‐mediated secretory cell replacement

Emmerson, Elaine ; May, Alison J ; Berthoin, Lionel ; Cruz‐Pacheco, Noel ; Nathan, Sara ; Mattingly, Aaron J ; Chang, Jolie L ; Ryan, William R ; Tward, Aaron D ; Knox, Sarah M

England: EMBO Press

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