Lipid-Based Research in Developing Autotherapies

In 2017, the National Institute of Dental and Craniofacial Research (NIDCR) launched NIDCR 2030, a strategic visioning initiative designed to advance dental, oral, and craniofacial research over the next 15 years.

Improving the development of autotherapies—treatments based on the body’s natural ability to heal and protect itself—is one of the 5 goals outlined in this initiative.

In a symposium hosted by NIDCR held on January 25, 2018, a panel of speakers discussed some of these therapies and how they can enhance the body’s innate healing ability.

Edward Botchwey, PhD, Associate Professor, Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Atlanta, and Director, Laboratory for Immuno-Regenerative Engineering, Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech, shared some strategies that he believes are underutilized in this area.

In particular, he highlighted the important role of lipid-based research in the development of different therapies, particularly in the autotherapy space.

In the immunobiology of tissue injury, macrophages are innate immune cells that are key regulators of tissue repair and regeneration. They play important roles in guiding vascular remodeling, stimulating local stem and progenitor cells, and influencing the structural repair of tissues such as skeletal muscle.

According to Dr. Botchwey, after inflammatory macrophages are initially recruited to the site of muscle injury, they switch their phenotype to become repair macrophages, by a mechanism that is partly regulated by CD4 T cells. Repair macrophages also produce soluble signaling factors to help determine the fate of endogenous satellite or stem cell populations in skeletal muscle, he added, guiding them to either proliferate or differentiate into skeletal muscle cells.

“Part of what we know happens in aging,” said Dr. Botchwey, “is that some of the mechanisms that regulate the transition to pro-regenerative repair macrophages get disrupted.” This can lead to persistence of some chronic inflammatory cells and ultimately disrupt the role that some other cell populations play, he explained.

With regard to the role of lipid-based research in this area, Dr. Botchwey noted that some lipid receptors overexpress certain subtypes of bioactive signaling lipids. This is especially true of sphingosine-1-phosphate (S1P) receptor-3 (S1P₃,) he said.

“So, we can direct small molecules at S1P₃ to increase the frequency of classical monocyte recruitment into the muscle tissue,” he emphasized. “And we have been able to show that classical monocytes have a predisposition to differentiate toward the repair macrophage phenotype.”

Dr. Botchwey said that after delivering materials loaded with a small molecule directed at S1P₃ to injured muscle, use of flow cytometry has demonstrated an increase in the numbers of non-classical monocytes, repair macrophages, and muscle satellite cells in the regenerating tissue.

“Using small molecules that are directed at some of these lipid receptors can, therefore, change the immune profile in muscle tissue to one that is more prone to regeneration,” he explained.

Furthermore, use of whole-mount microscopy has also shown that certain autonomous mechanisms in the inflammatory cells are directing the assembly of the regenerating muscle fibers in a way that is not only highly functional, but is also more aligned with the primary axis of the muscle.

“By loading the injured muscle with the small molecule, not only do we get more muscle tissue, and more highly-aligned muscle tissue, but it also starts to guide the developing extracellular matrix along the dominant axis of the muscle,” said Dr. Botchwey. “It couples the immunobiology with some of the desired remodeling that we want to see in the tissue, and this is consistent with tapping into endogenous repair responses.”

He went on to highlight some collaborative work that his lab is conducting, that aims to reduce the problem of oronasal fistula formation after cleft palate repair. The study aims to develop materials that harness pro-regenerative inflammatory responses and direct them to the sites of regeneration after cleft palate repair—"in a way that uses what those repair macrophages know how to do, to reform some of the more complicated tissue structures,” said Dr. Botchwey.

Finally, he introduced another class of bioactive lipid molecules known as resolvins. These molecules have a variety of effects in directing the immune response after implantation, he noted. “If we look at the pattern of the neutrophils infiltrating the new tissue, we find certain subtypes that know where to go.” Dr. Botchwey emphasized that these neutrophils are pro-angiogenic and infiltrate some of the microvascular networks and adopt perivascular locations in a way that may be important for subsequent remodeling in the tissue.

Resolvins also have a significant effect on increasing the profile of pro-regenerative cytokines in the tissue, including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), and interleukin-4 (IL-4), which are anti-inflammatory and pro-angiogenic. This is important because salivary levels of factors such as VEGF after cleft palate repair have been suggested to play an important role in some of the wound repair responses, he added.

Lipid-based research and technologies, such as these, thus have the ability to help transform healthcare, concluded Dr. Botchwey.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.