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α-Gal Nanoparticles in CNS Trauma: II. Immunomodulation Following Spinal Cord Injury (SCI) Improves Functional Outcomes

  • Original Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

Previous investigations have shown that local application of nanoparticles presenting the carbohydrate moiety galactose-α-1,3-galactose (α-gal epitopes) enhance wound healing by activating the complement system and recruiting pro-healing macrophages to the injury site. Our companion in vitro paper suggest α-gal epitopes can similarly recruit and polarize human microglia toward a pro-healing phenotype. In this continuation study, we investigate the in vivo implications of α-gal nanoparticle administration directly to the injured spinal cord.

METHODS:

α-Gal knock-out (KO) mice subjected to spinal cord crush were injected either with saline (control) or with α-gal nanoparticles immediately following injury. Animals were assessed longitudinally with neurobehavioral and histological endpoints.

RESULTS:

Mice injected with α-gal nanoparticles showed increased recruitment of anti-inflammatory macrophages to the injection site in conjunction with increased production of anti-inflammatory markers and a reduction in apoptosis. Further, the treated group showed increased axonal infiltration into the lesion, a reduction in reactive astrocyte populations and increased angiogenesis. These results translated into improved sensorimotor metrics versus the control group.

CONCLUSIONS:

Application of α-gal nanoparticles after spinal cord injury (SCI) induces a pro-healing inflammatory response resulting in neuroprotection, improved axonal ingrowth into the lesion and enhanced sensorimotor recovery. The data shows α-gal nanoparticles may be a promising avenue for further study in CNS trauma.

Graphical abstract

Putative mechanism of therapeutic action by α-gal nanoparticles. A. Nanoparticles injected into the injured cord bind to anti-Gal antibodies leaked from ruptured capillaries. The binding of anti-Gal to α-gal epitopes on the α-gal nanoparticles activates the complement system to release complement cleavage chemotactic peptides such as C5a, C3a that recruit macrophages and microglia. These recruited cells bind to the anti-Gal coated α-gal nanoparticles and are further polarized into the M2 state. B. Recruited M2 macrophages and microglia secrete neuroprotective and pro-healing factors to promote tissue repair, neovascularization and axonal regeneration (C.).

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Notes

  1. Abbreviation: SCI-spinal cord injury.

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Acknowledgements

We thank Christa Crain (Center for Comparative Translational Research (CCTR) Senior Research Technician) for assistance during surgeries. We thank Purdue University Histology Research Laboratory (Victor Bernal-Crespo and Mackenzie J McIntosh), a core facility of the NIH-funded Indiana Clinical and Translational Science Institute for histology work. This research was partly funded by the State of Indiana and Clinical and Translational Sciences Institute (CTSI, Indiana State Department of Health (Grant # 204200 to JL) and National Institute of Neurological Disorders and Stroke R21 (No. 1R21NS115094-01). We thank Purdue Animal Behavior Core for the use of the animal behavioral equipment.

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Authors and Affiliations

  1. Center for Paralysis Research, Purdue University, West Lafayette, IN, 47907, USA

    Bhavani Gopalakrishnan, Megan Saenger, Noah J. Burket, Manjari S. Lokender, Kaitlyn M. Wolfe, Samantha J. Husak, Collin J. Stark, August Dunbar, Riyi Shi & Jianming Li

  2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA

    Bhavani Gopalakrishnan, Luis Solorio & Riyi Shi

  3. Department of Medicine, Rush University Medical Center, Chicago, IL, USA

    Uri Galili

  4. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, USA

    Wendy Koss

  5. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA

    Abigail Cox

  6. Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA

    Riyi Shi & Jianming Li

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  1. Bhavani Gopalakrishnan
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Gopalakrishnan, B., Galili, U., Saenger, M. et al. α-Gal Nanoparticles in CNS Trauma: II. Immunomodulation Following Spinal Cord Injury (SCI) Improves Functional Outcomes. Tissue Eng Regen Med 21, 437–453 (2024). https://doi.org/10.1007/s13770-023-00616-y

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