Between Fate Choice and Self-Renewal—Heterogeneity of Adult Neural Crest-Derived Stem Cells

Abstract

Stem cells of the neural crest (NC) vitally participate to embryonic development, but also remain in distinct niches as quiescent neural crest-derived stem cell (NCSC) pools into adulthood. Although NCSC-populations share a high capacity for self-renewal and differentiation resulting in promising preclinical applications within the last two decades, inter- and intrapopulational differences exist in terms of their expression signatures and regenerative capability. Differentiation and self-renewal of stem cells in developmental and regenerative contexts are partially regulated by the niche or culture condition and further influenced by single cell decision processes, making cell-to-cell variation and heterogeneity critical for understanding adult stem cell populations. The present review summarizes current knowledge of the cellular heterogeneity within NCSC-populations located in distinct craniofacial and trunk niches including the nasal cavity, olfactory bulb, oral tissues or skin. We shed light on the impact of intrapopulational heterogeneity on fate specifications and plasticity of NCSCs in their niches in vivo as well as during in vitro culture. We further discuss underlying molecular regulators determining fate specifications of NCSCs, suggesting a regulatory network including NF-κB and NC-related transcription factors like SLUG and SOX9 accompanied by Wnt- and MAPK-signaling to orchestrate NCSC stemness and differentiation. In summary, adult NCSCs show a broad heterogeneity on the level of the donor and the donors’ sex, the cell population and the single stem cell directly impacting their differentiation capability and fate choices in vivo and in vitro. The findings discussed here emphasize heterogeneity of NCSCs as a crucial parameter for understanding their role in tissue homeostasis and regeneration and for improving their applicability in regenerative medicine.

Inter- and intrapopulational heterogeneity of characteristic markers in adult human neural crest-derived stem cells

“…A following RT-PCR analysis revealed the presence of transcripts for GAPDH, eEF2 and Vimentin in the ten-cells-sample as well as in all three single cell approaches (Figure 1 E). Further transcriptional profiling revealed the heterogenous expression of the NCSC-markers S100, Snail and Twist, the latter being key players in EMT and highly important in the determination of NCSC-fate (reviewed in 2 ). In particular, S100 gene expression was detectable in the 10-cell-sample and in two out of three single-cell-samples.…”

“…In accordance to our findings, a range of studies reported intrapopulational variations of NCSCs, namely between clonally grown NCSC-cultures from the same population. The NCSC-clones were shown to strongly vary in their differentiation potential and molecular profile (reviewed in 2 ). In particular, Singhatanadgit and coworkers reported a highly heterogeneous differentiation potential between clonal human periodontal ligament stem cell cultures, which varied from sole osteogenic to multilineage differentiation 33 .…”

“…After undergoing epithelial to mesenchymal transition (EMT), neural crest cells (NCCs) migrate in range of developing tissues and contribute to development by guiding patterning and by differentiation. Amongst others, NCCs give rise to most parts of the craniofacial skeleton, enteric neurons of the foregut and stomach or sympathetic ganglia and melanocytes in the trunk (reviewed in 2–4 ). After participating to embryonic development, pools of NCCs remain as adult neural crest-derived stem cells (NCSCs) in various tissues including the skin 5 , hair follicles 6 , carotid body 7 , heart 8,9 , palatum 10 or nasal cavity 11–13 (reviewed in 2,3 ).…”

“…Adult NCSCs share a broad differentiation potential particularly into mesodermal and ectodermal derivates as well as the expression of characteristic markers. These marker proteins include the intermediate filament Nestin and the calcium binding protein S100 as well as NC-related transcription factors (TF) like Twist or Slug, which belong to group of TF enabling EMT and therefore migration of embryonic NCCs (reviewed in 2,3 ). Their developmental potential and accessibility makes NCSCs promising candidates for regenerative medicine 14,15 and pharmacological research 16,17 .…”

“…Their developmental potential and accessibility makes NCSCs promising candidates for regenerative medicine 14,15 and pharmacological research 16,17 . Despite similarities in differentiation capacity and marker expression, increasing evidences show a remaining heterogeneity between different NCSC-populations (reviewed in 2 ). In this regard, we very recently observed an interpopulational heterogeneity between craniofacial and cardiac NCSCs.…”