While our most deadly chronic diseases are complex and varied, many of them share at least one quality: a depletion of healthy cells that our organs and other tissues depend on to function properly. This includes cardiomyocytes that power our hearts, hepatocytes that perform multiple tasks in the liver, and kidney cells that filter and balance our blood.
It’s no surprise then that scientists hope to replenish healthy cell populations as root cause treatments for heart disease, liver disease, and other conditions. One strategy is cell transplantation, an approach that involves implanting healthy cells into damaged bodily locations. While this can be done through traditional surgery, a less-invasive strategy involves injecting cells directly in a solution like saline. The drawback to this less-invasive method? The vast majority of cells don’t survive the injection.
Shot from a syringe, and free floating in a turbulent solution, cells are left unprotected from threats, like frictional shear force, which can deform cells flowing in layers and rip apart their membranes. Those that do reach their destination remain untethered from the disease site, making it less likely they will successfully engraft without a supportive structure and the cues that such a nurturing environment provides.
New Ways to Promote Cell Engraftment
In recent years, the emergence of injectable biomaterials has offered new ways to promote cell engraftment. However, some classes of these synthetic polymer-based tools come with risks like toxicity and immune rejection. More natural types of injectable biomaterials can be friendlier to cells, but are generally less reproducibly sourced nor tunable, limiting their potential clinical usefulness.
Now, a paper from the DeForest Research Group at the University of Washington describes a promising innovation: a recombinant protein-based biomaterial that shields encapsulated cells from the damaging effects of extensional flow during injection. The research, published in the journal Advanced Science, was led by ISCRM faculty member Cole DeForest, PhD, an Associate Professor of Chemical Engineering and Bioengineering, in collaboration with ISCRM Director Chuck Murry, MD, PhD and ISCRM faculty member Kelly Stevens, PhD. The co-first authors of the paper are Jennifer Bennett, a former Chemical Engineering MS student and Dr. Mary O’Kelly Boit, PhD a former Chemical Engineering PhD student, both of whom contributed to the study in the DeForest Research Group as part of their thesis projects.
“Our protein formulation has several specific features,” explains DeForest. “Most importantly, the material is formed from a single protein component that is produced recombinantly; it can be produced at scale, with essentially no batch-to-batch variability, offering reproducibility while dramatically lowering barriers to FDA approval. Moreover, the bulk of the protein is based off an intrinsically disordered protein called XTEN that has been evolved to have essentially no immune response.”
In this system developed by DeForest and his team, cells are embedded in protein-based hydrogels, which is then loaded into the back of a syringe. As the solution flows through the needle, the gel liquifies before ultimately resolidifying when the cells safely reach their destination. DeForest uses ketchup as an analogy. At the bottom of the bottle, ketchup behaves like a solid. When subjected to force, like a squeeze, it flows out of the bottle in a more liquid state but returns to a more solid-like state when it lands on your plate.
To put it simply, the protein-based biomaterial makes it possible to control the flow of the injection while protecting cells from the forces of that flow.
Injecting Heart and Liver Cells
It is a welcome development for Murry, whose lab is on a mission to remuscularize injured hearts by engrafting stem cell-derived cardiomyocytes after a heart attack.
“I’ve spent most of my career trying to regenerate the human heart using injectable therapies,” says Murry. “Transplantation is a huge stress to cells, subjecting them to brutal mechanical forces and delivering them to an inhospitable, diseased environment. Right now, more than 90% of the cells we deliver die from these stresses. This tunable protein hydrogel protects our cells during delivery and gives them a temporary niche, allowing better survival and integration with the host tissue. This is a big improvement over existing approaches that could be adapted readily for clinical trials of cell therapy.”
In the investigation, the researchers demonstrated that cardiomyocytes injected into dishes using the protein-based biomaterial fared better than cells injected in saline. The team partnered with the Stevens Lab to show the same results were possible with liver cells and kidney cells when they were injected into mice. The next steps are to track functional improvements over long periods of time and to test whether engraftment occurs when cells are injected into actual damaged heart, liver, and kidney tissues.
“It’s exciting to see years of work finally being published,” says Dr. O’Kelly Boit. “This recombinant protein-based hydrogel system excels where other gels (e.g. matrigel) fail. The clearly defined composition, lack of batch-to-batch variability, and reliability of a perfectly defined final product give it an easier route to FDA approval and fill a clear gap in current technologies available on the market. It was a team effort between me and Jenny and the DeForest Research Group and we look forward to seeing how it will continue to be used in to advance future discoveries in the upcoming years.”
Looking further ahead, DeForest speaks to the need for the tool detailed in the study. “There are thousands of ongoing clinical trials that involve injecting cells, either from one part of a person’s body to another, or from a donor to a recipient. There’s good reason to believe that these therapies could benefit from a biomaterial-mediated process like this one. It feels like the field is wide open across all arenas of cell transplantation.”
Acknowledgements:
This work was supported by a CAREER Award (DMR 1652141, C.A.D.) from the National Science Foundation, a Maximizing Investigators’ Research Award (R35GM138036, C.A.D.) and additional awards (R01HL146868, C.E.M.; R01HL148081, 22 C.E.M; R01DK128551, K.R.S.) from the National Institutes of Health, and an Allen Distinguished Investigator Award, a Paul G. Allen Frontiers Group advised grant of the Paul G. Allen Family Foundation (K.R.S.). Student fellowship support was provided from the National Science Foundation (DGE-2140004, N.E.G.) and the National Institutes of Health (1F31HL152626-01, M.O.B; T32EB001650, M.O.B.)