The estimated 44 million Americans who suffer from osteoporosis might benefit if scientists could direct adult mesenchymal stem cells (MSCs) from the bloodstream to the bone marrow, where they are able to develop into osteoblasts producing healthy, new bone.
For the past eight years, Robert Sackstein, a bone marrow transplant physician and HMS associate professor of dermatology at Brigham and Women’s Hospital, has been searching for ways to accomplish this by modifying the surface of MSCs so they dock on a receptor found on blood vessels within the marrow.
“Twenty years ago, we had no clue how stem cells migrated into the marrow; we now know a great deal,” Sackstein said.
In a mouse study appearing online Jan. 13 in Nature Medicine and in the February print issue, lead author Sackstein and colleagues describe the chemical engineering of human MSCs ex vivo. The researchers injected the cells intravenously into the animals, where they migrated to the bone marrow and formed bone cells.
Sackstein began this research investigating hematopoietic stem cell–homing molecules—proteins that function like GPS devices to direct cell migration. His work identified a novel glycoform of CD44 called hematopoietic cell E-selectin/L-selectin ligand (HCELL) that is found on the surface of human hematopoietic stem cells. HCELL avidly binds to E-selectin, a molecule found on the lining of blood vessels at sites of tissue injury. Simultaneously, other labs found that E-selectin is continuously expressed on specialized vessels within the bone marrow and is responsible for attracting stem cells.
Since E-selectin acts as a beacon for recruitment of cells to the bone marrow, Sackstein searched for a molecule on human MSCs that could bind to it. It turned out that MSCs express a modified version of CD44 that is one sugar, a fucose, short of being HCELL. Sackstein realized that if he fucosylated the surface CD44 on MSCs into HCELL, he might be able to direct MSCs to the marrow and achieve bone growth.
“It’s remarkable that you can take one single sugar, put it on a protein, and change the entire capacity of that cell to home,” Sackstein said.
He then found a way to selectively catalyze fucosylation of CD44 without causing toxicity to the cells. He decorated CD44 with the missing fucose, injected the human MSCs into mice, and watched as the cells migrated to E-selectin in the bone marrow within one hour. HCELL expression remained stable for 24 hours, but declined within 96 hours, presumably due to turnover of surface protein.
Patches of bone appeared in the mice within weeks. “This is the first time a human mesenchymal stem cell has migrated in blood flow to a bone tissue in an animal model and actually made bone,” Sackstein said.
