New discoveries about the formation of fetal blood stem cells that have been made independently by medical engineers and medical researchers at the University of New South Wales (UNSW) in Sydney could one day eliminate the need for blood stem cell donors.
These advances are part of a move in regenerative medicine toward using “induced pluripotent stem cells” to treat disease. This is where stem cells are reverse engineered from adult tissue cells rather than using live human or animal embryos.
Although we knew Induced pluripotent stem cells since 2006However, researchers still have much to learn about how to safely and artificially mimic cell differentiation in the human body in the laboratory for the purposes of delivering targeted medical therapy.
Pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. A somatic cell is any biological cell that forms the body of a multicellular organism other than a gamete, germ cell, placental cell, or undifferentiated stem cell.
University of New South Wales researchers recently completed two studies in the field that shed new light on not only how precursors to blood stem cells occur in animals and humans, but how they can be artificially stimulated.
One study was published on September 13, 2022 in the journal cell reports by scientists from the University of New South Wales’ School of Biomedical Engineering. They show how simulating a beating fetal heart using a microfluidic device in the lab led to the development of human blood stem cells, stem cells on the verge of becoming blood stem cells.
In another article recently published in Nature Cell BiologyResearchers from the University of New South Wales Medicine and Health have revealed the identity of cells in the embryos of mice that are responsible for forming blood stem cells.
Both studies are important steps toward understanding how, when, where and which cells participate in the formation of blood stem cells. In the future, this knowledge could be used to help cancer patients, among others, who have undergone high doses of radiation and chemotherapy, to replenish depleted blood stem cells.
In the detailed study in cell reportsLead author Dr. Jingjing Li and fellow researchers described how a microfluidic system infused blood stem cells produced from an embryonic stem cell line to mimic a fetus’s beating heart and circulatory conditions.
In the past few decades, she said, biomedical engineers have attempted to make blood stem cells in lab dishes to solve the problem of a shortage of blood stem cells for donors. But no one has been able to achieve this yet.
“Part of the problem is that we still don’t fully understand all of the processes that occur in the microenvironment during embryonic development that lead to the formation of blood stem cells around day 32 in embryonic development,” said Dr. Lee.
“So we made a device that simulates the heartbeat, blood circulation and the orbital vibration system that causes shear stress — or friction — to blood cells as they move through or around the device in a dish.”
These systems promoted the development of blood stem cells that can differentiate into different blood components – white blood cells, red blood cells, platelets, and others. They were excited to see this same process – known as hematopoiesis – repeated in the device.
Study co-author Professor Robert Nordon said he was surprised that the device not only created blood stem cell precursors that went on to produce differentiated blood cells, but also created cells of the fetal heart environment tissue that are essential for this process.
“The thing that amazes me about this is that blood stem cells, when they form in the fetus, form in the wall of a main blood vessel called the aorta. And they basically come out of that aorta and go into the circulation, and then they go to the liver and form what’s called final hematopoiesis, or final blood composition.
“The formation of the aorta and then the cells actually exiting from that aorta into the circulation, that’s the critical step required to generate these cells.”
“What we’ve shown is that we can create a cell that can make all the different types of blood cells. We’ve also shown that it’s closely related to cells lining the aorta – so we know its origin is correct – and that it multiplies,” A/Prof. Nordon said.
The researchers are cautiously optimistic about their achievement in mimicking fetal heart disease with a mechanical device. They hope this is a step toward solving the challenges that limit regenerative medical treatments today: lack of donor blood stem cells, rejection of donor tissue cells, and ethical issues related to the use of IVF embryos.
“Blood stem cells used in transplantation require donors of the same tissue type as the patient,” A/Prof. Nordon said.
“Manufacturing blood stem cells from pluripotent stem cell lineages would solve this problem without the need for tissue-compatible donors that provide ample supplies for treating leukemias or genetic diseases.”
“We are working to scale up the manufacture of these cells using bioreactors,” Dr. Lee added.
solve the puzzle
Meanwhile, working independently of Dr. Lee and A/Prof. Nordon, University of New South Wales Professor John Pemanda of Medicine and Health and Dr Vashi Chandrakanthan have been conducting their own research on how blood stem cells are formed in fetuses.
In their study of mice, the researchers looked for the mechanism used naturally in mammals to produce blood stem cells from cells that line blood vessels, known as endothelial cells.
“This process was already known to occur in mammalian embryos as the endothelial cells lining the aorta change into blood cells during hematopoiesis,” Professor Pimanda said.
“But the identity of the cells that regulate this process has hitherto been a mystery.”
Professor Pimanda and Dr Chandrakanthan describe in their paper how they solved this puzzle by identifying the cells in the fetus that can convert fetal and adult endothelial cells into blood cells. The cells – known as Mesp1-derived PDGFRA+ stromal cells – reside under the aorta, surrounding only the aorta in a very narrow window during embryonic development.
“Our research showed that when endothelial cells from the fetus or adult are mixed with ‘Mesp1-derived PDGFRA+ stromal cells’ – they start making blood stem cells.”
While more research is needed before this can be translated into clinical practice – including confirming the findings in human cells – the discovery could provide a potential new tool for generating graftable hematopoietic cells.
“Using your own cells to generate blood stem cells could eliminate the need for donor blood transfusions or stem cell transplants. Unlocking the mechanisms used by nature brings us one step closer to achieving this goal,” said Professor Pemanda.
“Mimicry of the Embryonic Circulation Enhances Hoxa Status and Human Blood Development” by Jingjing Li, Osmond Lau, Freya F. Provires, Yuan Wang, Kajal Choudhury, Ziqi Yang, Nonna Farbehi, Elizabeth S. Ng, Edward J. Stanley, Richard B. Harvey, Andrew J. Elephante, and Robert E. Nordon, Sept. 13 2022, cell reports.
DOI: 10.1016 / j.celrep.2022.111339
“PDGFRA Derived Medium Skin+ Cells regulate the emergence of hematopoietic stem cells in the dorsal aorta” by Vashi Chandrakanthan, Prunella Rurimpande, Fabio Zanini, Diego Chacon, Jake Olivier, Swabna Joshi, Yong Chan Kang, Kathy Knzevic, Yizhou Huang, Kyaw Qiao, Reema A. Ashwin Unnikrishnan, Daniel Carter, Brendan Lee, Chris Brownlee, Karl Bauer, Robert Brink, Simon Mendes Ferrer, Gregory Enikolopov, William Walsh, Berthold Guttgens, Samir Tawdie, Dominic Beck and John E. Pemanda, July 28, 2022, Nature Cell Biology.
DOI: 10.1038 / s41556-022-00955-3
Funding: National Health and Medical Research Council, Stem Cells Australia, Stafford Fox Medical Research Foundation, Novo Nordisk