Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles

Akihiro J. Matsuoka; Zafar A. Sayed; Nicholas Stephanopoulos; Eric J. Berns; Anil R. Wadhwani; Zachery D. Morrissey; Duncan M. Chadly; Shun Kobayashi; Alexandra N. Edelbrock; Tomoji Mashimo; Charles A. Miller; Tammy L. McGuire; Samuel I. Stupp; John A. Kessler

doi:10.1371/journal.pone.0190150

Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles

Akihiro J. Matsuoka^*, Zafar A. Sayed, Nicholas Stephanopoulos, Eric J. Berns, Anil R. Wadhwani, Zachery D. Morrissey, Duncan M. Chadly, Shun Kobayashi, Alexandra N. Edelbrock, Tomoji Mashimo, Charles A. Miller, Tammy L. McGuire, Samuel I. Stupp, John A. Kessler

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration.

Original language	English (US)
Article number	e0190150
Journal	PloS one
Volume	12
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0190150
State	Published - Dec 2017

Funding

This work was supported by the American Otological Society Clinician Scientist Award (AJM), the Triological Society/American College of Surgeons Clinician Scientist Award (AJM), the Department of Otolaryngology of Northwestern University (AJM), an NIH K08 Clinician Scientist Award K08 DC13829-02 (AJM), an NIH Ruth L. Kirschstein NRSA postdoctoral fellowship under Award # (1F32NS077728-01A1) (NS), a Graduate Research Fellowship from the National Science Foundation (ANE), the Northwestern University Center for Regenerative Nanomedicine through a CRN Catalyst Award (SIS), and an NIH P30 NS081774 (JAK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Dr. Moses V. Chao at New York University for kindly providing us with his p75NTR antibody; Evangelos Kiskinis, Ph.D. and Lyuba Lyass, Ph.D. at Northwestern University Stem Cell Core Facility; Wensheng Liu, M.D. at Northwestern University Imaging Core Facility; Yumiko Kobayashi, Mikoto Kobayashi, and Dr. Joseph T. Bass, M.D., Ph.D (NU) for assistance in RT-qPCR; Dr. Chris Gouveia (Stanford University) for assistance with surgeries on XSCID rats, and Dr. Jennifer L. Best (NU) and Dr. Sean A. Mutchnick (Wayne State University) for their expertise on our graphics. Special thanks are given to Dr. Zaida Alvarez Pinto (NU) for the provision of the IKVAV-PA gels; Dr. Chian-Yu Peng (NU) for qPCR analysis on our EGFP+ hESCs; Dr. Karl R. Koehler (Indiana University) for suggestion on antibody of PAX8 for immunocytochemistry; Dr. Steven T. Kosak (NU) and Dr. Vasil Garat (NU) for help in hESC culture. Finally, A.J.M. acknowledges the support and encouragement of his late father, Tetsuo Joseph Matsuoka, M.D., D.M.Sc.

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Matsuoka, A. J., Sayed, Z. A., Stephanopoulos, N., Berns, E. J., Wadhwani, A. R., Morrissey, Z. D., Chadly, D. M., Kobayashi, S., Edelbrock, A. N., Mashimo, T., Miller, C. A., McGuire, T. L., Stupp, S. I., & Kessler, J. A. (2017). Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles. PloS one, 12(12), Article e0190150. https://doi.org/10.1371/journal.pone.0190150

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abstract = "The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration.",

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AU - Wadhwani, Anil R.

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AU - Chadly, Duncan M.

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AU - Mashimo, Tomoji

AU - Miller, Charles A.

AU - McGuire, Tammy L.

AU - Stupp, Samuel I.

AU - Kessler, John A.

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Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles

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