Biomimicry and Regenerative Therapeutics

Regenerative medicine holds great hope for patients in the future, and two accomplished researchers discussed their work in the field at the March 25 Forum at the Beth Israel Deaconess Medical Center.

Jeffrey Karp, PhD, spoke on “Biomimicry: Nature as Model, Measure and Mentor.” He is an instructor in medicine and health, science and technology at Harvard Medical School and Brigham and Women’s Hospital; and director, Laboratory for Advanced Biomaterials and Stem Cell-based Therapeutics, BWH.

Moderator for his presentation was Frederick Schoen, MD, PhD, professor of pathology and health sciences and technology, Harvard Medical School; director of cardiac pathology and executive vice-chairman, Department of Pathology, Brigham and Women’s Hospital; and CIMIT site miner at BWH.

Presenting on the topic of “Steering Stem Cells to Treat Osteoporosis,” was Robert Sackstein, MD, PhD, associate professor of dermatology and of medicine, Harvard Medical School; head, the Translational Research Program of the Bone Marrow Transplantation Unit, Massachusetts General Hospital; Bone Marrow Transplant Physician at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute.

Moderator was Charles Vacanti, MD, anesthesiologist-in-chief, Leroy D. Vandam/Benjamin G. Covino Professor of Anaesthesia, Harvard Medical School; director, Laboratories for Tissue Engineering and Regenerative Medicine, Brigham and Women’s Hospital.

Dr. Karp discussed his work in the field of biomedical adhesives using nano and microscale approaches. Much of his study is based on understanding the mobility of the gecko, a form of lizard. He said geckos attach to smooth vertical surfaces and support their weight on a single toe. Dr. Karp indicated this principle could be useful in understanding that evolved designs in nature offer opportunities for advances in biomedical engineering.

He also discussed the creation of materials to capture cells mimicking the vascular endothelium’s ability to initiate cell rolling in viscous shear flow. Surface engineering through covalent immobilization of selectins can achieve long-term precise control over cell rolling, which may be useful for capturing and separating cells for diagnostic and therapeutic applications.

Dr. Sackstein discussed the notion that successful clinical implementation of stem cell-based regenerative therapeutics depends on the ability to deliver stem cells to sites where they are needed. His lab has developed a platform technology called "glycosyltransferase-programmed stereosubstitution,” or GPS, for custom-modifying CD44 glycans to create HCELL (hematopoietic cell E-/L-selectin ligand) on the surface of living cells. He suggested GPS technology could have major implications in therapy of generalized bone diseases such as osteoporosis, and may also be exploited for stem-cell based regenerative therapeutics for non-skeletal diseases.

Steering Stem Cells to Treat Osteoporosis

As the median age of the world population increases, degenerative diseases will become more common, and regenerative therapy will become increasingly important.  Osteoporosis, a disease characterized by thinning of the bones, affects around 300 million people worldwide and may affect one billion people by 2050.  In patients with osteoporosis, bone fractures are common and sometimes even lethal.  Contrary to what one might think, the bones in one’s body are always changing and are always being renovated.  Osteoporosis occurs when osteoclasts, cells that destroy bone, become more active than osteoblasts, cells that create bone.  Osteoblasts develop from mesenchymal stem cells, and the number of mesenchymal stem cells in the body decreases with age.  Certain researchers have attempted to boost the body’s supply of stem cells by locally injecting stem cells, but this technique leaves much to be desired.  It can damage tissue, and it cannot be used to treat diseases in hard-to-reach organs or systemic diseases such as osteoporosis.  In almost all cases, it would be safer and more effective to allow stem cells to reach their destinations via a vascular route. 

Researchers in the lab of Robert Sackstein of Harvard Medical School are attempting to come up with a way to direct mesenchymal stem cells to the bone marrow.  Their system is based on the fact that the bone marrow constitutively expresses e-selectins, a group of adhesion proteins.  A potent ligand for e-selectins is HCELL, or hematopoietic cell E-/L-selectin ligand.  HCELL can be made from the transmembrane glycoprotein CD44 by adding a few sugar molecules.  Like most cells, mesenchymal stem cells express CD44 but do not express HCELL.  Dr. Sackstein’s team has developed a method called glucosyltransferase-programmed stereosubstitution (GPS) that uses non-toxic enzymes to convert CD44 into HCELL.  Mesenchymal stem cells subjected to GPS become tagged for absorption in the bone marrow.  Dr. Sackstein’s group has found that injecting human HCELL-bearing mesenchymal stem cells into mice results in the homing of these cells to the bone marrow and in the subsequent deposition of human bone.  The GPS method being developed in the Sackstein lab will hopefully lead to a regenerative therapy for osteoporosis.  The technique could also be used, with modifications, to target stem cells to a variety of tissues, and its simplicity may someday enable it to be used in the third world.

   

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