Research Article

Priming mesenchymal stromal cells with neurotrophic factors boosts the neuro-regenerative potential of their secretome

Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, 412115, India

Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, 412115, India

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Aditya Nachanekar

Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, 412115, India

Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, 412115, India

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Vaijayanti Kale

https://orcid.org/0000-0001-7498-7563

Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, 412115, India

Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, 412115, India

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Anuradha Vaidya

*Author for correspondence:

E-mail Address: anuradha.vaidya@ssbs.edu.in

https://orcid.org/0000-0001-7451-7414

Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, 412115, India

Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, 412115, India

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Published Online:23 Mar 2023https://doi.org/10.2217/rme-2022-0201

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Abstract

Aim: To explore the neuroprotective potential of the secretome (conditioned medium, CM) derived from neurotrophic factors-primed mesenchymal stromal cells (MSCs; primed CM) using an endoplasmic reticulum (ER) stress-induced in vitro model system. Methods: Establishment of ER-stressed in vitro model, immunofluorescence microscopy, real-time PCR, western blot. Results: Exposure of ER-stressed Neuro-2a cells to the primed-CM significantly restored the neurite outgrowth parameters and improved the expression of neuronal markers like Tubb3 and Map2a in them compared with the naive CM. Primed CM also suppressed the induction of apoptotic markers Bax and Sirt1, inflammatory markers Cox2 and NF-κB, and stress kinases such as p38 and SAPK/JNK in the stress-induced cells. Conclusion: The secretome from primed MSCs significantly restored ER stress-induced loss of neuro-regenesis.

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Plain language summary

Endoplasmic reticulum (ER) stress-mediated accumulation of misfolded protein is one of the causes involved in the onset of several neurodegenerative diseases (ND). Under physiological conditions, ER stress activates the unfolded protein response (UPR) that repairs the misfolded proteins. However, if the ER stress becomes chronic, the UPR fails to repair the misfolded proteins leading to disease conditions such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, etc. Most in vitro systems are based on the infliction of acute ER stress on the target cells, which kills them, and thus, are not physiologically relevant models, as their neuro-regeneration is not possible. Here, we have developed a physiologically relevant in vitro model system, wherein we exposed Neuro-2a cells to an ER stress inducer which significantly affected their neuro-regenesis without killing them. These dysfunctional cells were then used to assess the effect of secretome (conditioned medium, CM) derived from mesenchymal stromal cells (MSCs) primed or not with neurotrophic factors. We found that priming of MSCs with neurotrophic factors enhances their neuroprotective potential. We demonstrate that when primed CM is given either as a single dose or in multiple doses, it restores neuro-regenesis and protects the stressed Neuro-2a cells from cell death. More importantly, the restoration of neuro-regenesis by primed CM is significantly higher as compared with the naive CM. These results clearly underscore the importance of priming the MSCs with neurotrophic factors for developing more effective therapeutic strategies to combat ND.

Tweetable abstract

Priming MSCs with neurotrophic factors boosts their neuroprotective potential. This strategy offers scope for developing competent cell-free therapies for the treatment of neurodegenerative diseases.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 18, No. 4

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Received 30 November 2022

Accepted 2 March 2023

Published online 23 March 2023

Published in print April 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/rme-2022-0201

Author contributions

P Teli: Experimental work, data analysis and interpretation & writing – original draft preparation. A Nachanekar: Experimental work, data analysis and interpretation & writing – original draft preparation.V Kale: Conceptualization, data interpretation, reviewing & editing. A Vaidya: Conceptualization, visualization, methodology, funding acquisition, data interpretation, writing - reviewing & editing, supervision.

Acknowledgments

The authors would like to thank Symbiosis Centre for Research & Innovation (SCRI), Symbiosis International (Deemed University) (SIU), Pune, India, for providing Junior Research Fellowship (JRF) to PT and infrastructural support. The authors would also like to thank the Experimental Animal Facility of Symbiosis School of Biological Sciences (SSBS), SIU for their relentless support.

Financial & competing interests disclosure

Financial support was provided by Symbiosis Centre for Research & Innovation (SCRI), Symbiosis International (Deemed University) (SIU), Pune, India, under Major Research Project (MJRP), Grant no: SIU/SCRI/MJRP/19-20/1516-C. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

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