BWH researchers ‘unlock’ key to targeting stem cells to specific tissues
One of the biggest barriers to effective cell therapy is the problem of targeting cells to tissues of interest, but researchers at Brigham and Women’s Hospital (BWH) have devised an approach to address this challenge
Likening this approach to a "lock and key," the BWH havechemically incorporated homing receptors onto the surface of cells. Using aplatform approach that preserves the mesenchymal stem cell (MSC) phenotype anddoes not require genetic manipulation, they modified the surface of MSCs with ananometer-scale polymer construct containing sialyl Lewisx (SLeX) that is foundon the surface of leukocytes and mediates cell rolling within inflamed tissue.The SLeX engineered MSCs exhibited a robust rolling response on inflamedendothelium in vivo and homed toinflamed tissue with higher efficiency, compared to native MSCs.
"Essentially, the blood vessels in specific tissues all havecertain 'locks' and 'keys,'" explains Dr. Jeffrey M. Karp, co-director of theRegenerative Therapeutics Center at BWH. "By knowing these 'locks,' we couldattach the 'keys' to the surface of cells. As they circulate through thebloodstream, they only engage to the corresponding cells."
Karp, who is also a principal faculty member of the HarvardStem Cell Institute, was one of the authors of a study describing thisapproach, "Engineered Cell Honing," which was published in the Oct. 27 onlineedition of the American Society of Hematology journal Blood. Karp's colleagues on the study included researchers from theMassachusetts General Hospital, the Massachusetts Institute of Technology(MIT), Harvard Medical School, the Harvard Stem Cell Institute and TuftsUniversity.
The team is full of analogies to describe their approach:"By knowing the 'zip code' of the blood vessels in specific tissues, we canprogram the 'address' onto the surface of the cells to potentially target themwith high efficiencies," Karp adds.
The finding will go a long way in addressing many of thechallenges associated with targeting stem cells to specific tissues—what Karpcalls "the big unmet need of stem cell research." While conventional celltherapies that include local administration of cells can be useful, they aretypically more invasive, with limited potential for multiple doses. For example,"when treating heart attacks or heart failure, injecting the cells directlyinto the heart can be an invasive procedure, and typically this approach canonly be performed once," Karp says.
Systemic infusion is desired, says Karp, as it minimizes theinvasiveness of cell therapy and maximizes practical aspects of repeated doses.
"We're getting to a point in time where one can obtainalmost unlimited quantities of almost any cell type in the lab—but what I thinkis really the biggest limitation to moving cell therapies to the clinic isbeing able to deliver cells to targeted tissues in the body, while maintaininghigh survival and efficacy rates. We posed the question: Can we target cells tospecific tissues using a non-viral approach that is chemical in nature? To dothis, we covalently modified the cell surface using a very simple approach atambient conditions. We chemically attached to the cell surface a ligand thatcan interact with something expressed in inflammation."
The researchers concluded that, as the understanding of themechanisms of cell trafficking grows, the ability to improve homing to specifictissues through engineered approaches should significantly enhance cell therapyby reducing the invasiveness of local administration, permitting repeat dosing andpotentially reducing the number of cells required to achieve a therapeuticeffect, ultimately providing better outcomes for patients.
According to Karp, this approach can be used to systemicallytarget bone-producing cells to the bone marrow to treat osteoporosis,cardiomyocytes to the heart to treat ischemic tissue, neural stem cells to thebrain to treat Parkinson's disease or endothelial progenitor cells to sites ofperipheral vascular disease to promote formation of new blood vessels.
The approach will translate to the core technology of a newstem cell company, he adds.
"Most of the companies in this area have been focusedon obtaining the right cell type and then delivering that cell, but the problemis that there hasn't been much innovation in the delivery area of this sciencethat is critical," Karp says. "We are in the process of translating thistechnology and other cell modification approaches within a new startupcompany."