Abstract
Human mesenchymal stem cells (MSC) are multipotent stem cells, which are isolated from various sources. Currently, there is a worldwide interest for dental MSC to be used against neurodegenerative diseases, since they derive from the neural crest and express embryonic stem cell markers. This fact prompted us to explore their potential for neural trans-differentiation in culture. We employed all-trans-retinoic acid (ATRA) and 2-(3-ethylureido)-6-methylpyridine (UDP-4) to induce neural differentiation of human MSC from the dental apical papilla (SCAP). The SCAP were exposed to either agent separately and assessed for proliferation, viability, morphology, and gene expression of the following neural-specific markers: neuron-specific enolase (ENO2), neurofibromin 1 (NF1), choline acetyltransferase (CHAT), tyrosine hydroxylase (TH), and the vesicular GABA transporter (SLC32A1). They were also assessed for the expression of glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN) by immunofluorescence. ATRA or UDP-4 treatment inhibited the cell growth and promoted limited cell death, but to a different extent. The addition of the neuroprotective agent recombinant human erythropoietin-alpha (rhEPO-α) enhanced the UDP-4-inducing capacity for more than three weeks. ATRA or UDP-4 treatment significantly upregulated ENO2 and NF1 expression, indicating neuronal differentiation. Moreover, the ATRA treatment significantly induced the upregulation of the GABAergic-specific SLC32A1, while the UDP-4 treatment led to the significant upregulation of the adrenergic-specific TH. The UDP-4 treatment induced the expression of NeuN and GFAP after four and three weeks, respectively, while the ATRA-treatment did not. Our findings indicate that SCAP can be differentiated into neural-like cells after treatment with ATRA or UDP-4 by exhibiting a disparate pattern of differentiation. Therefore, UDP-4 is suggested here as a new potent neural-differentiation-inducing compound, which, when combined with rhEPO-α, could lay the foundation for robust stem-cell-based therapies of neurodegeneration.
Highlights
Regenerative medicine has been a rapidly growing field of medicine, aiming to treat degenerative disorders with gene- and cell-based advanced-therapy medicinal products (ATMPs) [1,2]
Mesenchymal stem cells (MSC) have attracted worldwide attention for autologous and mostly allogeneic cell-based therapies over the last years due to their unique properties, such as the following: (a) their immunomodulatory capacity and immunosuppressive potential (b) their ability to differentiate into different phenotypes, as mentioned above [5,6] (c) their capability to secrete over 40 growth factors and cytokines that contribute to tissue microenvironment and niche formation [6]
We investigate here whether human stem cells from the apical papilla (SCAP) can be trans-differentiated into neural cells in cultures containing 15% fetal calf serum (FCS) supplemented with all-trans-retinoic acid (ATRA) or UDP-4, an ureido-derivative of pyridine substituted with a 2-(3-ethylureido) group at position 6 [16]
Summary
Regenerative medicine has been a rapidly growing field of medicine, aiming to treat degenerative disorders with gene- and cell-based advanced-therapy medicinal products (ATMPs) [1,2]. Biomolecules 2022, 12, 218 conditions and/or the tissue microenvironment [3,4,5]. MSC have attracted worldwide attention for autologous and mostly allogeneic cell-based therapies over the last years due to their unique properties, such as the following: (a) their immunomodulatory capacity and immunosuppressive potential (b) their ability to differentiate into different phenotypes, as mentioned above [5,6] (c) their capability to secrete over 40 growth factors and cytokines that contribute to tissue microenvironment and niche formation (secretome) [6]. Several studies were carried out to differentiate MSC of dental origin, as well as that of various other sources [7,8], by growing them in a culture medium with fetal calf serum (FCS), or even under serum free [9] conditions, using macromolecular factors, such as EGF, FGF, and BDNF, as neuronal cell-differentiation inducers [10,11,12]. Human SCAP originally derive from the neural crest and express the mesenchymal precursor cell markers
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