From UCLA: “Stem cell advance could be key step toward treating deadly blood diseases”

UCLA

May 17, 2016
Mirabai Vogt-James

Vincenzo Calvanese, Dr. Hanna Mikkola and Diana Dou are working toward being able to create hematopoietic stem cells in the lab so that they are a perfect match for transplant recipients. UCLA Broad Stem Cell Research Center

Scientists at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have made several discoveries that are critically important to understanding how blood stem cells are created and maintained — both in the body and in the laboratory.

The findings may lead to the creation of a new source of life-saving blood-forming stem cells, which could help people with a wide range of blood diseases by reducing many of the risks of bone marrow transplants. Thousands of people each year in the U.S. alone are diagnosed with diseases that could be treated with the procedure.

The study*, led by senior author Dr. Hanna Mikkola and first co-authors Vincenzo Calvanese and Diana Dou, was published in the journal Nature Cell Biology.

Blood-forming stem cells, or hematopoietic stem cells, are found in the bone marrow and can create any type of blood cell. The researchers pinpointed the function of a cluster of specialized genes that play a key role in creating and preserving hematopoietic stem cells and identified the process by which those genes are activated during human development and in the laboratory.

For decades, doctors have used bone marrow transplants to treat people with diseases of the blood or immune system. One complicating factor has always been that certain proteins in the donor’s and recipient’s cells must match so that the donor’s immune system doesn’t reject the transplant. But finding a perfect match can be difficult, and the process is risky for both donors and recipients.

The UCLA research could provide a way to create patient-specific hematopoietic stem cells, which would reduce some of the challenges associated with bone marrow transplants.

“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Mikkola, a professor of molecular, cell and developmental biology in the UCLA College and a member of the UCLA Jonsson Comprehensive Cancer Center. “One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”

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Pluripotent stem cells are capable of becoming any cell type in the human body. However, some tissue-specific stem cells, such as hematopoietic stem cells, have been difficult to derive from pluripotent stem cells, creating a fundamental challenge associated with the creation of stem cell-based medical treatments.

Mikkola and the research team first tried to create hematopoietic stem cells in the lab from pluripotent stem cells. When they compared the lab-created cells to the hematopoietic stem cells found in the body, they found that an important cluster of genes, called HOXA genes, weren’t activated in the lab-created cells. They also showed that HOXA genes help hematopoietic stem cells maintain their stem cell attributes, such as the ability to generate more copies of themselves, which is a defining characteristic of any kind of stem cell.

“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Calvanese, an assistant project scientist in Mikkola’s lab. “Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”

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The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes, so they could try to replicate the process in the lab. They found that mimicking the effects of retinoic acid, a compound derived from vitamin A, acts like a switch that turns on the HOXA genes during the development of hematopoietic stem cells.

“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Dou, a graduate student in Mikkola’s lab. “This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”

The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created hematopoietic stem cells that have — and maintain — all of the functions of human hematopoietic stem cells.

The research was supported by grants from the California Institute for Regenerative Medicine, the National Institutes of Health (RO1 DK100959, P01 GM081621, PO1 HL073104 and HL086345), the National Science Foundation Graduate Research Fellowship Program, the Leukemia and Lymphoma Society, and the UCLA Broad Stem Cell Research Center and its training programs, which are supported in part by the Shaffer Family Foundation and the Rose Hills Foundation.

*Science paper:
Medial HOXA genes demarcate haematopoietic stem cell fate during human development

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From U Washington: “Stem cell research gets undergrads out of classroom”

University of Washington

03.23.2016
McKenna Princing

Deepkiran Singh, a UW junior in biochemistry, demonstrates pipetting, a lab technique to measure or transfer liquids.

UW undergraduate Randy Lu grasps a pair of tweezers in each hand. His fingers making imperceptible movements as he dissects the tiny abdomen of a fruit fly. The tweezers and Lu’s hands look garishly large next to the insect, which is a mere speck in a glass dish. Lu has to look through a microscope in order to see it in detail.

Leaning over Lu’s shoulders is his mentor and fellow undergraduate Debra Del Castillo, who guides him as he learns how to master the light touch necessary to complete such delicate work. Lu is not the first student Del Castillo has mentored: As program coordinator for an undergraduate research project that brings students into the lab of UW biochemistry professor, Hannele Ruohola-Baker at UW Medicine’s Institute for Stem Cell and Regenerative Medicine Research. Del Castillo has overseen the work of dozens of students for the past two years.

The students contribute to an ongoing study examining a protective signal daughter cells send back to their stem cells in the germ line of fruit flies. The signal seems to help the stem cells survive even when they are targeted with chemotherapy or radiation. Researchers believe this phenomenon could explain why some cancers are so difficult to eradicate.

To combat this, researchers are screening nearly 1,600 different molecules to see if any prevent the daughter cells from sending that signal. Molecules that do this could be turned into a drug that would prevent tumors from regenerating.

The screen is an intensive process composed of multiple steps—a perfect opportunity, Del Castillo feels, to teach undergraduates how real-world science often works.

Debra Del Castillo looks through a confocal microscope to check undergraduate Randy Lu’s progress dissecting flies. McKenna Princing

“Most undergraduate programs have labs where the experiments are highly optimized, where you know what the results are going to be,” she said.

Ruohola-Baker testified to the explorative nature of the work students partake in.

“You are the first one in the world to find the answer for your question when you come in the morning to develop that film, study those stem cells in the confocal microscope or analyze their level of RNA after the drug treatment,” she said. “Your job is to go to the edge of human knowledge and push beyond.”

The step-by-step process looks like this: Students feed one of the small molecules in question to a days-old fruit fly, then sacrifice the insect, isolate the affected cells and put them through a lengthy immunohistochemistry protocol. Next come dissection and analysis to determine whether or not the molecule interfered with the protective signal. Students are usually trained for three to four months before they are allowed to complete the process on their own and analyze results.

“I have to work with them a lot to get the confidence to make that call, because they’re young and they’ve never done this before, and they’re afraid they’ve done it wrong,” Del Castillo said.

She, too, had to develop confidence when she first joined the project. Currently a post-baccalaureate studying biochemistry, she took a winding path to get where she is now: A degree and then a job in engineering, followed by many years of caregiving, first for her children and then for her aunt, who was diagnosed with Huntington’s disease.

“It all ended at once; I went from caregiving to nothing, so I thought I’d go back to school,” she said. “In high school, I had wanted to be a doctor or medical researcher, but because I came from a family where all these strange things happened—my mother died at 27, my grandmother got schizophrenia at age 50—I didn’t feel like I had the support to go for it when I was young.”

She eventually found out that Huntington’s runs in the family. She was tested and does not carry the gene. That knowledge spurred her to pursue medical research. She wants to do studies that might lead to new ways to protect other people from disease. At North Seattle College she fell in love with cellular biology and organic chemistry. There she participated in her first research project, an experience that ultimately inspired her to bring undergraduates into the lab at UW.

Currently, 14 undergraduates are involved in the study; each works up to 25 hours a week. One student, biochemistry junior Deepkiran Singh, wants to become a gynecological surgeon and feels contributing to research helps her prepare for that goal.

“Working with your hands, being precise, is really important,” she said. “Before, I was shaky; I had to learn. And it’s good to have lab experience when you go into medicine. I have more of a sense of freedom here [than in a classroom].”

Del Castillo believes the work will have lasting effects on students.

“Young people spend so much time in school, but this really prepares them for real-world jobs,” she said. “To see the principles of science and biochemistry at work is so profound: It sets the stage for them to have a realistic understanding of what it takes to get valid, reproducible results and to do good science.”

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From phys.org: “Scientists generate a new type of human stem cell that has half a genome”

phys.org

March 16, 2016
No writer credit found

Scientists from The Hebrew University of Jerusalem, Columbia University Medical Center (CUMC) and The New York Stem Cell Foundation Research Institute (NYSCF) have succeeded in generating a new type of embryonic stem cell that carries a single copy of the human genome, instead of the two copies typically found in normal stem cells. The scientists reported their findings today in the journal Nature.

A haploid cell with 23 chromosomes (left), and a diploid cell with 46 chromosomes (right). Credit: Columbia University Medical Center/Hebrew University

The stem cells described in this paper are the first human cells that are known to be capable of cell division with just one copy of the parent cell’s genome.

Human cells are considered ‘diploid’ because they inherit two sets of chromosomes, 46 in total, 23 from the mother and 23 from the father. The only exceptions are reproductive (egg and sperm) cells, known as ‘haploid’ cells because they contain a single set of 23 chromosomes. These haploid cells cannot divide to make more eggs and sperm.

Previous efforts to generate embryonic stem cells using human egg cells had resulted in diploid stem cells. In this study, the scientists triggered unfertilized human egg cells into dividing. They then highlighted the DNA with a fluorescent dye and isolated the haploid stem cells, which were scattered among the more populous diploid cells.

The researchers showed that these haploid stem cells were pluripotent—meaning they were able to differentiate into many other cell types, including nerve, heart, and pancreatic cells—while retaining a single set of chromosomes.

“This study has given us a new type of human stem cell that will have an important impact on human genetic and medical research,” said Nissim Benvenisty, MD, PhD, Director of the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University of Jerusalem and principal co-author of the study. “These cells will provide researchers with a novel tool for improving our understanding of human development, and the reasons why we reproduce sexually, instead of from a single parent.”

The researchers were also able to show that by virtue of having just a single copy of a gene to target, haploid human cells may constitute a powerful tool for genetic screens. Being able to affect single-copy genes in haploid human stem cells has the potential to facilitate genetic analysis in biomedical fields such as cancer research, precision and regenerative medicine.

“One of the greatest advantages of using haploid human cells is that it is much easier to edit their genes,” explained Ido Sagi, the PhD student who led the research at the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University of Jerusalem. In diploid cells, detecting the biological effects of a single-copy mutation is difficult, because the other copy is normal and serves as “backup.”

Since the stem cells described in this study were a genetic match to the egg cell donor, they could also be used to develop cell-based therapies for diseases such as blindness, diabetes, or other conditions in which genetically identical cells offer a therapeutic advantage. Because their genetic content is equivalent to germ cells, they might also be useful for reproductive purposes.

“This work is an outstanding example of how collaborations between different institutions, on different continents, can solve fundamental problems in biomedicine,” said Dieter Egli, PhD, principal co-author of the study, and Assistant Professor of Developmental Cell Biology in Pediatrics at Columbia University Medical Center and a Senior Research Fellow at the NYSCF Research Institute and a NYSCF-Robertson Investigator.

The research, supported by The New York Stem Cell Foundation, the New York State Stem Cell Science Program, and by the Azrieli Foundation, underscores the importance of private philanthropy in advancing cutting-edge science.

More information: Ido Sagi et al. Derivation and differentiation of haploid human embryonic stem cells, Nature (2016). DOI: 10.1038/nature17408

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From Rochester: “Scientists Discover Stem Cells Capable of Repairing Skull, Face Bones”

University of Rochester

February 01, 2016
Media Contact
Leslie Orr
(585) 275-5774

A team of Rochester scientists has, for the first time, identified and isolated a stem cell population capable of skull formation and craniofacial bone repair in mice—achieving an important step toward using stem cells for bone reconstruction of the face and head in the future, according to a new paper in Nature Communications.

The photo shows a blue-stained stem cell and a red-stained stem cell that each generated new bones cells after transplantation

Senior author Wei Hsu, Ph.D., dean’s professor of Biomedical Genetics and a scientist at the Eastman Institute for Oral Health at theUniversity of Rochester Medical Center, said the goal is to better understand and find stem-cell therapy for a condition known as craniosynostosis, a skull deformity in infants. Craniosynostosis often leads to developmental delays and life-threatening elevated pressure in the brain.

Hsu believes his findings contribute to an emerging field involving tissue engineering that uses stem cells and other materials to invent superior ways to replace damaged craniofacial bones in humans due to congenital disease, trauma, or cancer surgery.

For years Hsu’s lab, including the study’s lead author, Takamitsu Maruyama, Ph.D., focused on the function of the Axin2 gene and a mutation that causes craniosynostosis in mice. Because of a unique expression pattern of the Axin2 gene in the skull, the lab then began investigating the activity of Axin2-expressing cells and their role in bone formation, repair and regeneration. Their latest evidence shows that stem cells central to skull formation are contained within Axin2 cell populations, comprising about 1 percent—and that the lab tests used to uncover the skeletal stem cells might also be useful to find bone diseases caused by stem cell abnormalities.

The team also confirmed that this population of stem cells is unique to bones of the head, and that separate and distinct stem cells are responsible for formation of long bones in the legs and other parts of the body, for example.

The National Institutes of Health and NYSTEM funded the research.

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