image: The new bioreactor that recapitulates blood flow behaves like a French Press coffee maker, pushing the flow up and down to generate turbulence that enhances platelet production from megakaryocytes. view more
Credit: Misaki Ouchida / Kyoto University
Blood flows through the body smoothly in order to transport its content throughout the body. In a new study seen in Cell, scientists at CiRA show unexpectedly that small levels of turbulence in the blood promotes the generation of platelets, the cells responsible for wound healing. Using this new information, they report a bioreactor that produces more than 100 billion platelets from iPS cells, a number that can be used to treat patients.
Blood transfusions are the oldest form of cell therapy and have been done for centuries. Platelets are blood cells that stop bleeding and have other healing factors. Platelet transfusions are common for patients undergoing surgery, cancer therapies, or suffering from platelet-related diseases. However, platelets taken from donors can only be stored for several days, which is why organizations like the Red Cross hold regular blood drives. While this approach is the global standard, with the number of aging populations increasing, many nations are anticipating severe donor shortages. Japan alone estimates that its platelet supplies will serve only four of every five patients in the next decade.
CiRA Professor Koji Eto, who is also Professor at the Chiba University School of Medicine, has been developing platelets using iPS cell technology to replace the dependency on donors. Platelets are extremely small fragments that blood flow breaks off the surface of much larger cells called megakaryocytes, much like washing debris off a car. Unlike platelets, megakaryocytes can be stored for long periods, but they are extremely rare in the body and therefore difficult to acquire from donors. Eto's research team has found a solution to this problem by making an almost unlimited supply of megakaryocytes from iPS cells.
To produce platelets from megakaryocytes, engineers constructed bioreactors that recapitulate blood flow. However, for regular patient care, more than 100 billion-order platelets are needed, and no bioreactor comes close to producing this amount.
"There has been lots of work on bioreactors, but they only used laminar flow. Nobody thought about turbulence," said Eto.
To reach the numbers needed for patient therapy, the new study shows that besides laminar flow, incorporating turbulent flow into the bioreactors is key.
This realization came from microscopic observations of blood flow in mice. While the blood flow was mostly laminar, Eto's team found turbulence was present around the megakaryocytes.
To generate turbulence, their new bioreactor behaves like a French Press coffee maker, pushing the flow up and down.
Further study revealed that the turbulence stimulates three mediators: macrophage migration inhibitory factor, insulin growth factor binding protein 2, and nardilysin, all of which were previously unknown to have a crucial role in platelet generation.
Dr. Naoshi Sugimoto, a hematologist and member of the lab who contributed to the study said, "we can use the mediators to make a specialized culture to improve the performance of the bioreactor."
Finally, the platelets were found to behave normally in mouse and rabbits, an important final step before using them in humans.
"Our goal is to produce platelets in the lab to replace human donors," said Eto.
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The paper "Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production" appeared 12 July 2018 in Cell with doi: 10.1016/j.cell.2018.06.011
About Center for iPS Cell Research and Application (CiRA)
CiRA was founded in 2008 and is devoted to the study of induced pluripotent stem cells (iPS cells) and other forms of cell reprogramming along with their medical applications. Since its inception, CiRA has been directed by Shinya Yamanaka, who earned the Nobel Prize in 2012 for his discovery of induced pluripotent stem cells (iPS cells). For more information, please see: https://www.cira.kyoto-u.ac.jp/e/index.html
Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centers, as well as facilities and offices around Japan and the world. For more information please see: http://www.kyoto-u.ac.jp/en
Journal
Cell