A major step toward growing kidneys

Cells that produce blood vessels have been identified and isolated, paving the way for tissue engineering.

In a significant step toward growing replacement kidneys, researchers at the University of Virginia School of Medicine have identified the cells that give rise to the blood vessels within the kidney.

It's a discovery of critical importance, as efforts to grow kidneys have long been frustrated by the inability to create the vasculature necessary for a functional organ.

Researchers also made the surprising find that when these vessels are created, so is the blood that fills them.

Until now, scientists had not known that the kidney was a blood-generating organ. Blood generation occurs within the kidney in fish, but this is a notable discovery in mammals.

Researchers have long been able to grow kidney tissue in a lab dish, even successfully forming various components of the organ. However, they have not been able to create the vessels that carry life-giving blood. Without that, there's no hope of creating a functional organ.

But by identifying the stem cells that develop into the vessels, UVA's Maria Luisa S. Sequeira-Lopez, MD, and her team have given scientists a target to manipulate so that one day they may be able to grow complete organs. By understanding the natural development of the vessels, they can seek to reproduce and control them.

The work is published online by the Journal of the American Society of Nephrology.

"We are very interested in knowing how the kidney vasculature develops. It's crucial. You cannot have a kidney without vasculature. It's very easy to grow in culture the tubular part of the kidney but not the vessels. This will be key, crucial, if we are thinking of replacement therapy or making a functioning kidney in the future from a patient's cells. If we don't understand how the normal vasculature develops, we cannot reproduce or force cells to make it."

Sequeira-Lopez, of the Department of Pediatrics and UVA's Child Health Research Center.

Sequeira-Lopez previously identified the cells that form the outer layer of the vessels. In her new discovery, she and her team identify the cells that form the inner layer. In addition, researcher Yan Hu noted, they identified an important molecule that regulates the development of the kidney vasculature.

"We finally found the precursor to these cells, so the next step is to determine the controllers," said Hu, a graduate student.

As they worked, Sequeira-Lopez and Hu noted something very unusual about the formation of the vessels in the kidney — as they formed, so did the blood they contained.

"A characteristic of this new precursor that we found is that it can also make blood cells. It not only makes the endothelial layer, the inner layer of the vessel, but it makes blood," Sequeira-Lopez said. "So at the time you make a new blood vessel, it's not that it's empty, but it has its content in it - the blood cells are inside."

Hu noted: "Rarely do researchers find this phenomenon in organs, and for the first time to identify it in the developing kidney."

Abstract
The close relationship between endothelial and hematopoietic precursors during early development of the vascular system suggested the possibility of a common yet elusive precursor for both cell types. Whether similar or related progenitors for endothelial and hematopoietic cells are present during organogenesis is unclear. Using inducible transgenic mice that specifically label endothelial and hematopoietic precursors, we performed fate-tracing studies combined with colony-forming assays and crosstransplantation studies. We identified a progenitor, marked by the expression of helix-loop-helix transcription factor stem cell leukemia (SCL/Tal1). During organogenesis of the kidney, SCL/Tal1+ progenitors gave rise to endothelium and blood precursors with multipotential colony-forming capacity. Furthermore, appropriate morphogenesis of the kidney vasculature, including glomerular capillary development, arterial mural cell coating, and lymphatic vessel development, required sphingosine 1-phosphate (S1P) signaling via the G protein–coupled S1P receptor 1 in these progenitors. Overall, these results show that SCL/Tal1+ progenitors with hemogenic capacity originate and differentiate within the early embryonic kidney by hemovasculogenesis (the concomitant formation of blood and vessels) and underscore the importance of the S1P pathway in vascular development.

The findings have been published online by the Journal of the American Society of Nephrology. The article was written by Hu, Minghong Li, Joachim R. Göthert, R. Ariel Gomez and Sequeira-Lopez.

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Dec 24, 2015   Fetal Timeline   Maternal Timeline   News   News Archive   

In 2013, Salk scientists grew human stem cells into early-stage ureteric buds,
or kidney structures responsible for reabsorbing water after toxins are filtered out.
They used mouse embryonic kidney cells (RED) to coax human stem cells to grow
into the mushroom-shaped (BLUE and GREEN) buds.

Image Credit: Salk Institute