From MedicalXpress, by Harvard University
Engineered miniature kidneys come of age
In recent years, researchers have created mini-organs known as organoids in the culture dish that contain many of the cell types and complex microarchitectures found in human organs, such as the kidney, liver, intestine, and even the brain. However, most organoids grown in vitro lack the vasculature required to provide oxygen and nutrients, remove metabolic waste, and facilitate communication between different cell types that drives their maturation into truly functional tissue building blocks.
For kidney organoids, this shortcoming prevents researchers from emulating key kidney functions in vitro, including blood filtration, reabsorption, and urine production. Creating robustly vascularized kidney organoids could enable better modeling of kidney diseases, enhance renal drug toxicity testing and, ultimately, lead to new building blocks for renal replacement therapies.
Now, a research team at the Wyss Institute for Biologically Inspired Engineering, the Harvard Paulson School of Engineering and Applied Sciences (SEAS), Brigham and Women's Hospital, and the Harvard Stem Cell Institute led by Jennifer Lewis and Ryuji Morizane has developed a powerful new approach as part of the Institute's new 3-D Organ Engineering Initiative. By exposing stem cell-derived organoids to fluidic shear stress, they were able to significantly expand organoid-derived vascular networks, and improve the maturation of kidney compartments in comparison to previous static culture methods. The work is published in Nature Methods.
In 2015, Ryuji Morizane and Joseph Bonventre developed a method that enabled them to derive 3-D kidney organoids from human pluripotent stem cells. "While our organoids and those generated in other laboratories contained large numbers of well-organized nephrons and primitive blood vessels, they still lacked pervasive vascular compartments with perfusable lumens," said co-corresponding author Morizane, M.D., Ph.D., Assistant Professor at Brigham and Women's Hospital and Harvard Medical School (HMS), and a member of the Harvard Stem Cell Institute.
More recently, researchers around the world have matured kidney organoids by implanting them into animals where they can connect to the host's vasculature in vivo. "For the first time, our study demonstrates that by exposing growing organoids to fluid flow, a mechanical cue known to play an important role for tissue development in the body, we can greatly enhance their vascularization and maturation in vitro," said Morizane.
To accomplish this feat, the team used expertise from the Lewis lab that has pioneered strategies to create vascularized human tissues, including 3-D kidney-on-chip models, using 3-D bioprinting that can be perfused and sustained for long durations. Based on these findings, they hypothesized that fluid flow could also promote the formation of blood vessels from precursor endothelial cells found in growing kidney organoids.
"We determined the right combination of underlying extracellular matrix, media additives, and fluidic shear stress under which human stem-cell derived organoids would flourish when grown in our 3-D-printed millifluidic chips," said Kimberly Homan, Ph.D., who with Navin Gupta, M.D., is a first author on the study. Gupta added that "the vascular networks form close to the epithelial structures that build the glomerular and tubular compartments, and in turn promote epithelial maturation. This integrated process works really like a two-way street." Homan is a Research Associate in Lewis' group at the Wyss Institute and SEAS, and Gupta is a Clinical Research Fellow working on Morizane's team at the Brigham.
The vessels growing on the 3-D-printed chips form an interconnected network with open lumens, which can be perfused with fluids as confirmed by directly imaging fluorescent beads moving freely through them. "We were excited to see that these vascularized glomerular and tubular structures develop through some of the same stages that nephrons experience during normal kidney development in vivo," said Homan.
"This important advance opens up new avenues for accurately testing drug toxicity in vitro in differentiated nephron compartments and modeling kidney diseases, like polycystic kidney disease, that affect specific structures and cell types using patient-derived stem cells as the starting point," said co-corresponding author Lewis, Sc.D., who is a Core Faculty member of the Wyss Institute and co-leader of its 3-D Organ Engineering Initiative. "Our method may pave the way to also vascularize other types of organoids, such as the liver organoids." Lewis is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS and a member of the Harvard Stem Cell Institute.
"This study is a great example of the importance of mechanobiology and the potential power of the Wyss Institute's 3-D Organ Engineering Initiative. It provides an important cornerstone for many efforts that aim to create functional human tissues de novo for research, pharmaceutical and tissue regenerative applications," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at SEAS.
Gift of Life
From Honey Latest, Australia , By Maddison Leach
Mum donates kidney to stranger after seeing a flyer at her son’s taekwondo classss
Amanda Hayhurst never expected that her life would be changed by a flyer, but just weeks after donating her kidney to a stranger, she couldn’t be happier about it.
The mother-of-two from Georgia, USA, was picking up her eldest son from a taekwondo class late last year when she spotted a flyer telling the story of a local single mum in desperate need of a kidney transplant.
“I knew before I finished reading that we were going to be a match,” Hayhurst, 32, told Good Morning America.
“I just knew it.”
But she didn’t know Vonchelle Knight, 50, the woman who had been on the waitlist for a kidney transplant for more than eight years.
Knight suffered from Polycystic Kidney Disease since 2004, a genetic disorder that slowly reduces kidney function and can eventually lead to kidney failure, as well as causing other complications such as high blood pressure when left untreated.
One of Knight’s daughters had posted the flyer as part of an ongoing effort to help find her mother a donor after years of waiting and unsuccessful matches.
Since 2013 Knight has had to spend nine hours each day on dialysis, hooked up the machine as she slept, and suffered constant fatigue and cramps.
Hayhurst knew none of this however, in fact the only thing she knew about Knight was that she was a single mother-of-two who needed a kidney – but for Hayhurst that was enough.
“If not me, who?” Hayhurst said of her decision, “She is on this list and none of her friends and family are a match.”
The young mum immediately began undergoing tests to see if she would be a suitable match, telling no one but her husband Marcus what she was planning, and in December of 2018 she was approved to be a living kidney donor for Knight.
She contacted Courtney Knight, the daughter who had posted the flyer, and the two went to Knight’s home to tell her the news.
“I knew God was telling me he had a blessing for me and it was going to be big,” Knight said of the years spent waiting for a donor.
“He just told me to be still and quiet and in time it would be revealed, then Amanda showed up and it was one of the greatest moments.”
“We cried for like two hours and just talked,” Hayhurst recalled of the moments after she first met Knight and told her they were a match.
“We talked and cried and I held her. It was just really sweet.”
The two women spent the next month bonding, even bringing their families together to celebrate Christmas, and successfully underwent surgery on 25 January.
“Having a baby for me was harder than this,” Hayhurst said, adding that after surgery she only felt minor abdominal pain and was released from hospital the following day.
Now she wants to spread awareness of living kidney donation and encourage more healthy young people like her to consider ‘sharing their spare’.
She’s shared the stories of countless other people in the US searching for kidney donors on her Facebook page, and even started Find Your Kidney Donor, a page dedicated to helping find donors for more people living with kidney disease.
“I feel like more people need to know more about it,” she said of living kidney donation.
In Australia living donations make up around a third of all kidney donations, and donors don’t need to be related to or even know the recipient.
Most physically healthy people are eligible to donate after undergoing testing, and donors can give their kidneys anonymously to a recipient on the transplant waitlist.
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