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Astrocyte-Like Cells Differentiated from Dental Pulp Stem Cells Protect Dopaminergic Neurons Against 6-Hydroxydopamine Toxicity

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Abstract

Dental pulp stem cells (DPSCs) are promising for use in neurodegenerative-diseases because of their neural crest origin. While neuronal differentiation of DPSCs has been shown, their plasticity towards astrocyte-like cells remains to be studied. We aimed to examine differentiation potential of DPSCs to astrocytes and their consequent neuroprotective role towards dopaminergic (DA) neurons under 6-hydroxydopamine (6-OHDA) toxicity. Induction of DPSCs to astrocytes with differentiation factors showed definitive increase in astrocyte-specific markers glial fibrillary acidic protein (GFAP), and excitatory amino acid transporter 2 along with glial calcium-binding protein S100β through FACS and immunofluorescence assays. RT-PCR and ELISA showed significant increase in BDNF and GDNF expression and secretion in astrocyte-differentiated DPSCs over naïve DPSCs. Neuroprotective role of these cells on DA neurons under 6-OHDA stress was evaluated by both contact and non-contact methods. FACS analysis of PKH26-stained SH-SY5Y homogenous cells in contact method and of TH immunopositive cells in primary midbrain culture in non-contact method both indicated higher survival of DA neurons in astrocyte-differentiated DPSCs over naïve DPSCs. Recovery of β-tubulin III and TH immunopositive cells was reduced in the presence of TrkB inhibitor, suggesting a key neuroprotective role of BDNF secretion by DPSCs. When nitric oxide (NO) release was inhibited by l-NAME in primary midbrain culture, BDNF release in co-culture under 6-OHDA stress reduced further in naïve DPSCs than in astrocyte-differentiated DPSCs, suggesting that BDNF release in naïve DPSCs is primarily regulated by paracrine signaling while for differentiated DPSCs, it is equally through autocrine and paracrine signaling with NO being the mediator. In conclusion, we suggest that DPSCs exposed to glial commitment cues exhibit substantial differentiation towards astrocyte-like cells with better neuroprotective activity against 6-OHDA toxicity than naïve DPSCs.

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Author notes

  1. Kavina Ganapathy and Indrani Datta contributed equally to this work.

Authors and Affiliations

  1. Department of Biophysics, National Institute of Mental Health and Neurosciences, P.B. No – 2900, Hosur Road, Bengaluru, Karnataka, 560029, India

    Kavina Ganapathy & Indrani Datta

  2. School of Regenerative Medicine, Manipal University, Bengaluru, Karnataka, 560065, India

    Kavina Ganapathy & Ramesh Bhonde

  3. Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411018, India

    Ramesh Bhonde

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  1. Kavina Ganapathy
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Correspondence to Indrani Datta.

Electronic Supplementary Material

Supplementary figure 1

FACS histograms for the astrocyte specific markers GFAP & EAAT2 along with glial calcium-binding protein S100β; neural commitment marker ASCL1; and neural crest marker HNK1 in DPSCs and astrocytes differentiated DPSCs at different day points of induction. (PNG 1166 kb)

High Resolution Image (TIF 493 kb)

Supplementary figure 2

FACS histograms of each cell population β tubulin III (total neuronal cells), GFAP (astrocytes) and TH (dopaminergic neurons) in the primary midbrain cells co-cultured with DPSC and astrocyte-differentiated DPSCs under 6-OHDA in comparison with primary midbrain cells in control and treated conditions. (PNG 1343 kb)

High Resolution Image (TIF 515 kb)

Supplementary figure 3

FACS histograms of each cell population with the TrkB inhibitor ANA12 A) β tubulin III (total neuronal cells) B) GFAP (astrocytes) and c) TH, (dopaminergic neurons) in the primary midbrain cells co-cultured with DPSC and astrocyte induced DPSCs under 6-OHDA. (PNG 673 kb)

High Resolution Image (TIF 293 kb)

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Ganapathy, K., Datta, I. & Bhonde, R. Astrocyte-Like Cells Differentiated from Dental Pulp Stem Cells Protect Dopaminergic Neurons Against 6-Hydroxydopamine Toxicity. Mol Neurobiol 56, 4395–4413 (2019). https://doi.org/10.1007/s12035-018-1367-3

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  • DOI: https://doi.org/10.1007/s12035-018-1367-3

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