You are here

| Neural Crest Stem Cells

Lgr5 Marks the Spot for Adult Neural Crest Stem Cells

Review of “Lgr5 marks neural crest derived multipotent oral stromal stem cells” from Stem Cells by Stuart P. Atkinson

Neural crest stem cells (NCSCs) are a self-renewing population of cells that have the ability to give rise to neurons, glia, fibroblasts, bone, cartilage, connective tissue and the dermis [1, 2]. Furthermore, various studies have found them to be present in a wide range of adult tissues. Researchers led by Agnieszka Kobielak (University of Warsaw, Poland) sought to discover whether NCSCs exist in the adult human oral mucosa and, if so, their exact location and role in normal tissue homeostasis. 

To achieve this, the group have employed the Wnt target gene Lgr5 [3] to study the presence of NCSCs in the tongue and oral mucosa and in mouse embryos to track them throughout development using in vivo lineage tracing. Their findings, reported in Stem Cells [4], suggest that NCSCs can be readily identified in the oral mucosa, giving the possibility of their isolation, cultivation and therapeutic use.

The study employed a previously developed reporter mouse which uses GFP as a surrogate marker for Lgr5 expression [3], which allowed the authors to show the presence of Lgr5-positive cells both in neural crest cells during early embryonic development (E9.5) and then in the tongue and oral mucosa of adult mice. A cross with another reporter mouse allowed the study to lineage trace Lgr5-positive cells, and this not only confirmed that Lgr5-positive cells had self-renewing capabilities, but also that they differentiated to give rise to stromal mucosa cells. Using the NC reporter mouse line Wnt1Cre [5], the study then confirmed that Lgr5-positive adult cells are neural crest derived, and so may represent adult NCSCs.

Excitingly, the group also showed that selected Lgr5-positive cells could be isolated and propagated in embryonic neural crest culture conditions [6], forming tightly packed, large colonies containing small cells with relatively undifferentiated morphology. At the RNA level, these cells resembled embryonic neural crest cells (expression of Sox9, Twist1, Snai1, Myc, Ets1, Crabp1, Epha2, and Itgb1) and had the ability to differentiate into cells of the neural crest lineage, including smooth muscle actin positive cells, glial cells and osteoblasts (See Figure). Finally, the authors demonstrated that Lgr5-positive cells assumed a mesenchymal fate in a de novo reconstitution assay and also played a role in tongue wound healing, so demonstrating the importance of Lgr5-positive cells in tissue homeostasis and a possible role for these cells in cell-based regenerative strategies.

The discovery of multipotent, self-renewing NCSCs in the adult may provide us with any easy to access and therapeutically relevant source of cells with multiple applications within regenerative medicine [7]. The question now has to be whether or not we can find similar cells in the human oral mucosa/tongue and whether these have similar characteristics.

References

  1. Morrison SJ, White PM, Zock C, et al. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 1999;96:737-749.
  2. Dupin E, Calloni G, Real C, et al. Neural crest progenitors and stem cells. C R Biol 2007;330:521-529.
  3. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007;449:1003-1007.
  4. Boddupally K, Wang G, Chen Y, et al. Lgr5 Marks Neural Crest Derived Multipotent Oral Stromal Stem Cells. Stem Cells 2016;34:720-731.
  5. Danielian PS, Muccino D, Rowitch DH, et al. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol 1998;8:1323-1326.
  6. Ishii M, Arias AC, Liu L, et al. A stable cranial neural crest cell line from mouse. Stem Cells Dev 2012;21:3069-3080.
  7. Kaltschmidt B, Kaltschmidt C, and Widera D Adult craniofacial stem cells: sources and relation to the neural crest. Stem Cell Rev 2012;8:658-671.