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Credit: John Perry
Researchers say they have uncovered early clues that better explain how hematopoietic stem cells (HSCs) are generated.
Their research, conducted in zebrafish, provides new insight regarding the role of JAM proteins and the Notch signaling pathway, which was already known to be critical for HSC generation.
The new findings may help clear the way to producing HSCs from human pluripotent precursors, according to the researchers.
David Traver, PhD, of the University of California, San Diego School of Medicine, and his colleagues recounted these findings in a letter to Nature. A similar study, which revealed the role of endotome cells in HSC generation, was also recently published as a letter to Nature.
“Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” Dr Traver said. “What has not been known is where, when, and how Notch signal transduction is mediated.”
Through experiments in zebrafish models, Dr Traver and his colleagues found the Notch signal is transduced into HSC precursor cells from signal-emitting cells in the somite much earlier in the process than previously anticipated.
Specifically, the team found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling.
When the researchers caused JAM proteins to lose function, Notch signaling and HSCs were also lost. When they enforced Notch signaling, the team rescued HSC development.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” Dr Traver said. “This has been due, in part, to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process.”
“Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling, in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.”
Dr Traver and his colleagues believe the findings may have far-reaching implications for the eventual development of HSC-based therapies for diseases such as leukemia and congenital blood disorders. 
Credit: John Perry
Researchers say they have uncovered early clues that better explain how hematopoietic stem cells (HSCs) are generated.
Their research, conducted in zebrafish, provides new insight regarding the role of JAM proteins and the Notch signaling pathway, which was already known to be critical for HSC generation.
The new findings may help clear the way to producing HSCs from human pluripotent precursors, according to the researchers.
David Traver, PhD, of the University of California, San Diego School of Medicine, and his colleagues recounted these findings in a letter to Nature. A similar study, which revealed the role of endotome cells in HSC generation, was also recently published as a letter to Nature.
“Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” Dr Traver said. “What has not been known is where, when, and how Notch signal transduction is mediated.”
Through experiments in zebrafish models, Dr Traver and his colleagues found the Notch signal is transduced into HSC precursor cells from signal-emitting cells in the somite much earlier in the process than previously anticipated.
Specifically, the team found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling.
When the researchers caused JAM proteins to lose function, Notch signaling and HSCs were also lost. When they enforced Notch signaling, the team rescued HSC development.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” Dr Traver said. “This has been due, in part, to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process.”
“Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling, in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.”
Dr Traver and his colleagues believe the findings may have far-reaching implications for the eventual development of HSC-based therapies for diseases such as leukemia and congenital blood disorders.
Credit: John Perry
Researchers say they have uncovered early clues that better explain how hematopoietic stem cells (HSCs) are generated.
Their research, conducted in zebrafish, provides new insight regarding the role of JAM proteins and the Notch signaling pathway, which was already known to be critical for HSC generation.
The new findings may help clear the way to producing HSCs from human pluripotent precursors, according to the researchers.
David Traver, PhD, of the University of California, San Diego School of Medicine, and his colleagues recounted these findings in a letter to Nature. A similar study, which revealed the role of endotome cells in HSC generation, was also recently published as a letter to Nature.
“Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” Dr Traver said. “What has not been known is where, when, and how Notch signal transduction is mediated.”
Through experiments in zebrafish models, Dr Traver and his colleagues found the Notch signal is transduced into HSC precursor cells from signal-emitting cells in the somite much earlier in the process than previously anticipated.
Specifically, the team found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling.
When the researchers caused JAM proteins to lose function, Notch signaling and HSCs were also lost. When they enforced Notch signaling, the team rescued HSC development.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” Dr Traver said. “This has been due, in part, to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process.”
“Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling, in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.”
Dr Traver and his colleagues believe the findings may have far-reaching implications for the eventual development of HSC-based therapies for diseases such as leukemia and congenital blood disorders.