Abstract
Neural crest (NC) cells play a central role in forming the peripheral nervous system, the craniofacial skeleton, and the pigmentation of the skin during development due to their broad multilineage differentiation potential into neurons, Schwann cells, melanocytes, and mesenchymal stem cells. Recently, we identified an easily accessible source of pluripotent NC stem cells from human inter‐follicular keratinocyte (KC) cultures (KC‐NC). In this work, we examined specific conditions for the derivation of NC from KC cultures. More specifically, we examined the role of two growth factors, FGF2 and IGF1, in NC proliferation and in expression of two potent NC transcription factors, Sox10 and FoxD3. Using specific chemical inhibitors, we uncovered that the downstream regulatory pathways AKT/PI3K, MEK/ERK, and JNK/cJun may be critical in Sox10 and FoxD3 regulation in KC‐NC. The TGF‐β1 pathway was also implicated in suppressing Sox10 expression and NC proliferation. In summary, our study shed light into the role of FGF2, IGF1, and TGF‐β1 on the induction of NC from KC cultures and the pathways that regulate Sox10 and FoxD3. We also established culture conditions for sustaining KC‐NC multipotency and, therefore, the potential of these cells for regenerative medicine and cellular therapies.
Highlights
Neural crest (NC) is an embryonic structure, unique to vertebrates, at the junction of neural and non-neural ectoderm, from which NC cells arise and migrate laterally along the length of developing neural tube
After the neuralectoderm folds to form the neural tube, NC stem cells develop a migratory phenotype and delaminate from its dorsal aspect.[2]. This mobility is made possible by the ability of NC cells to undergo epithelial to mesenchymal transition (EMT), enabling migration throughout the developing embryo, where they contribute to portions of the craniofacial skeleton, neurons, peripheral glia, cardiac outflow tract, smooth muscle cells, chondrocytes, adipocytes, melanocytes, and so forth.[1]
We focused on the role of growth factors and downstream signaling pathways that may be important in derivation of NC from human KC and identified the culture conditions that may be optimal for NC proliferation and expression of key transcription factors, Sox[10] and FoxD3, which have been shown to be critical for maintenance of the NC phenotype and the NC multilineage differentiation potential
Summary
Neural crest (NC) is an embryonic structure, unique to vertebrates, at the junction of neural and non-neural ectoderm, from which NC cells arise and migrate laterally along the length of developing neural tube. After the neuralectoderm folds to form the neural tube, NC stem cells develop a migratory phenotype and delaminate from its dorsal aspect.[2] This mobility is made possible by the ability of NC cells to undergo epithelial to mesenchymal transition (EMT), enabling migration throughout the developing embryo, where they contribute to portions of the craniofacial skeleton, neurons, peripheral glia, cardiac outflow tract, smooth muscle cells, chondrocytes, adipocytes, melanocytes, and so forth.[1] This was confirmed through the use of in vitro clonal cultures, where individual NC cells were isolated, expanded, and subjected to factors known to induce differentiation.[3] Regulation of such a transient population of cells requires a complex network of signaling pathways to maintain the stem cell-like state and control all subsequent cellular changes. We focused on the role of growth factors and downstream signaling pathways that may be important in derivation of NC from human KC and identified the culture conditions that may be optimal for NC proliferation and expression of key transcription factors, Sox[10] and FoxD3, which have been shown to be critical for maintenance of the NC phenotype and the NC multilineage differentiation potential
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