Stemness of mature cells

by Alexey Bersenev on December 28, 2013 · 0 comments

in other adult stem cells

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The series of studies, published this year, have changed a current dogma about mature cells plasticity and regeneration process. It was discovered, that mature cell types in different organs can possess stem cell-like qualities, namely self-renewal and differentiation, during tissue regeneration process.

What did we know about self-renewal beyond stem cells? We knew that T-cell memory subsets can self-renew via asymmetric division. We also knew, that tissue macrophages can self-renew. But we never called them “stem cells”. We didn’t know anything (or knew very little) about self-renewal and plasticity of mature differentiated cells outside of hematopoietic system. We thought it’s impossible – the cells are differentiated! Everything has changed this year. Besides tissue-resident macrophages, stem cell qualities of differentiated cells were described in the epithelium of stomach, lung and kidney.
Michael Sieweke and Judith Allen wrote in their review:

These findings challenge the classical view of tissue maintenance by adult tissue-specific stem cells and indicate that stem cell–like self-renewal mechanisms may be activated in mature differentiated cells.

Hans Clevers described a new marker Troy, which labels subset of gastric epithelial chief cells with stem-cell like properties.

In this study, we assess Troy as a marker of cells that contribute to tissue renewal in the gastric corpus. We find that Troy is expressed by a small subset of chief cells and parietal cells located at the gland base. Under steady-state conditions, these cells phenotypically fulfill all requirements of differentiated cells.

Using lineage tracing analysis, Clevers demonstrates that Troy+ cells can generate all types of differentiated cells of gastric epithelium. In vitro, Troy+ cells can make long-living gastric organoids. He concluded:

The unique property of the Troy+ cell as a fully differentiated cell with the capability to act as a multipotent stem cell represents a surprising example of plasticity in epithelial stem cell biology.

A group of researchers from Massachusetts General Hospital and Harvard University demonstrated that mature adult epithelial cells in the lung airway can spontaneously converted into stem cells in vivo:

After the ablation of airway stem cells, we observed a surprising increase in the proliferation of committed secretory cells. Subsequent lineage tracing demonstrated that the luminal secretory cells had dedifferentiated into basal stem cells.
This capacity of committed cells to dedifferentiate into stem cells may have a more general role in the regeneration of many tissues and in multiple disease states, notably cancer.

Benjamin Humphreys demonstrated that differentiated kidney epithelial cells repair injured proximal tubule. These cells were not only able to multiply many times to repair tissue, but also expressed stem cell markers:

… fully differentiated proximal tubule cells not only proliferate after injury, but they also upregulate apparent stem-cell markers. This study shows that epithelial dedifferentiation is responsible for repair of mouse proximal tubule, rather than an adult stem-cell population.

Very recent study, involved classical limb regeneration model in salamanders, demonstrated that different species could use different mechanisms for regeneration. Unlike axolotl, newts use a mechanism of dedifferentiation of mature myofibers in reparative regeneration of limb:

In the newt, myofiber fragmentation results in proliferating, PAX7− mononuclear cells in the blastema that give rise to the skeletal muscle in the new limb. In contrast, myofibers in axolotl do not generate proliferating cells, and do not contribute to newly regenerated muscle; instead, resident PAX7+ cells provide the regeneration activity.

So, dedifferentiation of mature cells could be universal mechanism of regeneration.

One may ask – why do we even need tissue resident stem cells for reparative regeneration? Well, it seem like plasticity of differentiated cells is not enough to fix tissue damage. Perhaps, different tissues use different mechanisms for regeneration – from stem cells only, from stem cells and mature cell reserve and from mature cells only. Possibly, it also depends on type of tissue damage.

So, recently discovered ability of mature cells to dedifferentiate and possess stem cell-like qualities, changes our current view and understanding of adult tissue homeostasis and regeneration. This phenomenon is also breaking a dogma about inability of differentiated cells to go back to embryonic state spontaneously. It will be interesting to look at difference in self-renewal mechanisms (pathways) in adult stem cells, differentiated tissue cells and cancer cells. Why self-renewal in tissue regeneration does not cause a cancer? And how can we use this knowledge to therapies development?

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