ACT to Start Clinical Trial of iPSC-Derived Platelets

Platelets are blood cells that help clot our blood when blood vessels are damaged. They are small cells, and are only about 20% of the diameter of red blood cells. There are typically about 150,000-350,000 platelets per microliter of blood. Despite these large numbers, platelets only compose a tiny fraction of the blood volume. As mentioned, the main function of platelets is to prevent bleeding. Platelets Platelets are produced in the bone marrow by the typical process of blood cell production. Hematopoietic stem cells in the bone marrow divide to renew and form a progenitor cell that differentiates into either a pro-erythrocytes, which becomes a red blood cell, or a promegakaryocyte. Promegakaryoyctes differentiate into megakaryocytes, which are the cells that form platelets. Platelets bud off the cytoplasm of the megakaryocytes. Consequently, platelets do not possess a nucleus. Each megakaryocyte produces between 5,000 and 10,000 platelets. Platelet differentiation Megakaryocyte and platelet production is regulated by a hormone called thrombopoietin, which is produced by the liver and kidneys. The average lifespan of circulating platelets is 5-9 days, and older platelets are destroyed by cells in the spleen and by Kupffer cells in the liver that gobble up the old platelets and recycle their components. Many platelets are held in reserve by the spleen, which are released when needed by contraction of the spleen, which is induced by the sympathetic nervous system (fight or flight response).

The cells that compose the inner surface of blood vessels normally inhibit platelet activation by producing various molecules, such as nitric oxide, and prostaglandin I2. Blood vessel cells also make a cell surface molecule called von Willebrand factor, which helps them adhere to the cable-like protein collagen that lies outside the blood vessels. Injury to blood vessels reduces the production of these inhibitory molecules and exposes the platelets and blood to collagen and von Willebrand factor (vWF). When the platelets contact collagen or vWF, they become activated. This activation manifests itself is several ways. First of all, the platelets dump the granules that they store. These granules contain several important molecules, but they also place new surfaced proteins on the outside of the platelets that help them clump together. Activated platelets also change their shape to become more spherical, and extensions of the surface form. This gives them a kind of star-shape.


Other molecules released from their granules include ADP, which is a platelet-activating molecule, the neurotransmitter serotonin, which induces blood vessels to constrict (this staunches blood loss), blood clotting factors (factors V and XIII for those who are interested), and some growth factors. Platelet activation also induces platelets to synthesize a molecule called thromboxane A2, which, like ADP, activates other platelets. Thus platelet activation is a self-amplifying event and gets more and more platelets involved in the act. I hope I have convinced you of the importance of platelets.

Some people have problems with insufficient numbers of platelets, and they have trouble properly clotting their blood.  Therefore, giving them more platelets is an excellent way to treat them, but a source of platelets must be found in order to give them to the patient. Enter the Massachusetts-based biotechnology company, ACT.  Advanced Cell Technologies from Marlborough, Mass., wants to test platelets made from reprogrammed cells; that is to say induced pluripotent stem cells.   Patients with some types of leukemia, anemia and other conditions need repeated infusions of platelets to avoid bleeding to death.  Additionally, the immune system of such patients can become sensitized to donated platelets, which compromises their effectiveness.

Platelets made from induced pluripotent stem cells (iPSCs) could overcome that problem because they were derived from a patient’s own cells. Platelets also seem to be the ideal cell for this technology because the platelets live for such s short time, they do not have a nucleus, and therefore, cannot cause tumors. Alan Michelson, a platelet researcher at Harvard Medical School and Boston Children’s Hospital who would lead a clinical trial in the U.S. studying ACT’s stem-cell derived platelets, said, “This would really be a dramatic advance in medicine, but it remains to be seen if this would be successful.”

Robert Lanza, ACT’s chief scientific officer, said that the company has the “capacity to make enough” platelets for the initial clinical trials but would “take time to scale up for widespread use.”  He added, “It doesn’t require any embryos. It doesn’t require eggs. It doesn’t require any destruction of embryos.” ACT has proposals for clinical trials and the company has said that testing could begin as early as the end of next year if regulators sign off.  The U.S. Food and Drug Administration has declined to comment, since federal rules prevent it from discussing any therapies that may be under development.

According to Lanza, the proposed U.S. trial would potentially infuse  normal platelets and stem-cell-derived platelets into eight patients and compare how well the cells functioned.  Because the platelets can be labeled, blood draws from the patients would determine if the iPSC-derived platelets behave like bona fide platelets.

According to Cynthia Dunbar, a stem-cell researcher at the National Heart, Lung and Blood Institute and editor of the journal Blood, if the iPSC-derived platelets worked like normal platelets, “the potential impact would be great.”

POSEIDON Clinical Trial Shows the Feasibility of Heart Patients Being Treated With Someone Else’s Mesenchymal Stem Cells

Joshua Hare from the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine has headed up the POSEIDON clinical trial. Poseidon stands for the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis Pilot Study (NCT01087996). The goal of this study was to examine the effects of mesenchymal stem cells on the hearts of patients who had suffered a heart attack some time ago and compare the effects of treating a patient with their own mesenchymal stem cells, or with those of a donor. Mesenchymal stem cells (MSCs) are known to not rile the immune system, but if they are implanted for a long period of time, there is a chance that they will elicit an immune response. However, there is evidence that the bone marrow quality of a patient decreases after a heart attack. Therefore, administering MSCs from a healthy donor might work even better than using a heart attack patient’s own MSCs.

In this trial, Hare and his colleagues took 31 patients who suffered from “ischemic cardiomyopathy,” and randomly gave them injections into their heart muscle of their own MSCs, or MSCs from a healthy donor. They monitored the patients for adverse effects and also monitored their heart function 1 year after MSC administration.

The results showed a low rate of adverse effects for both groups 30 days after treatment. One year after treatment, there were even fewer adverse effects. The patients who were given their own MSCs showed improvement over the distance walked in 6 minutes. These same patients also said that they had an increased quality of like. Both groups also showed some improvements in the remodeling of their hearts, which is the say that the enlargement of the heart was decreased. Unfortunately, there were no measurable improvements in heart function. Importantly, none of the patients who had received someone else’s MSCs showed a significant immune response against the implanted MSCs. One patient did show some antibodies against the implanted MSCs, but this is only 1/15 patients in the absence of any immunosuppression.

These results are modest, but they are good enough for a larger clinical trial. to that end, Hare will now engage in the ALLSTAR (Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration) study (NCT01458405) of 270 patients with ventricular dysfunction after a heart attack. These results are reasons for cautious optimism.