Blood formation: researchers engineer human bone marrow tissue

Scanning electron microscopy images confirm the deposition of an extracellular matrix which embeds cells, presumably of both stromal and blood origins. (Image: University of Basel)

Researchers have developed an artificial tissue in which human blood stem cells remain functional for a prolonged period of time. Scientists from the University of Basel, University Hospital Basel, and ETH Zurich have reported their findings in the scientific journal PNAS.


Every day in the bone marrow several billion blood cells are formed. This constant supply is ensured by blood stem cells located in special niches within the marrow. These stem cells can multiply and mature into red and white blood cells, which then leave the bone marrow and enter the bloodstream.

For several years, researchers have been trying to reproduce natural bone marrow in the laboratory in order to better understand the mechanisms of blood formation and to develop new therapies – such as for the treatment of leukemia.

However, this has proven to be extremely difficult because – in conventional in vitro models – the blood stem cells lose their ability to multiply and to differentiate into different types of blood cells.
A new kind of artificial bone marrow

Now, researchers have engineered an artificial bone marrow niche, in which the stem and progenitor cells are able to multiply for a period of several days. These findings were reported by researchers working under Professor Ivan Martin from the Department of Biomedicine at the University of Basel and University Hospital Basel and Professor Timm Schroeder from ETH Zurich’s Department of Biosystems Science and Engineering.

The researchers have developed an artificial tissue that mimics some of the complex biological properties of natural bone marrow niches. To do this, they combined human mesenchymal stromal cells with a porous, bone-like 3D scaffold made of a ceramic material in what is known as a perfusion bioreactor, which was used to combine biological and synthetic materials.

This gave rise to a structure covered with a stromal extracellular matrix embedding blood cells. In this respect, the artificial tissue had a very similar molecular structure to natural bone marrow niches, creating an environment in which the functionality of hematopoietic stem and progenitor cells could largely be maintained.

A tool for personalized research

The new technique could also be used to produce tailor-made bone marrow niches that have specific molecular properties and that allow the selective incorporation or removal of individual proteins.

This opens up a whole host of possibilities, from researching factors that influence blood formation in humans, to drug screening with a view to predicting how individual patients will respond to a certain treatment.

“We could use bone and bone marrow cells from patients to create an in vitro model of blood diseases such as leukemia, for example. Importantly, we could do this in an environment that consists exclusively of human cells and which incorporates conditions tailored to the specific individual,” explain Ivan Martin and Timm Schroeder.

Original source

Paul E. Bourgine, Thibaut Klein, Anna M. Paczulla, Takafumi Shimizu, Leo Kunz, Konstantinos D. Kokkaliaris, Daniel L. Coutu, Claudia Lengerke, Radek Skoda, Timm Schroeder, and Ivan Martin
In vitro biomimetic engineering of a human hematopoietic niche with functional properties
PNAS (2018), doi: 10.1073/pnas.1805440115

Further information
Prof. Dr. Ivan Martin, University of Basel / University Hospital Basel, Department of Biomedicine, tel. +41 61 265 23 84, email: ivan.martin@unibas.ch
Prof. Dr. Timm Schroeder, ETH Zurich, Department of Biosystems Science and Engineering, email: timm.schroeder@bsse.ethz.ch




Autor: UNIBAS
Fonte: UNIBAS
Sítio Online da Publicação: UNIBAS
Data de Publicação: 04/06/2018
Publicação Original: https://www.unibas.ch/en/News-Events/News/Uni-Research/Researchers-engineer-human-bone-marrow-tissue.html

Vitamin C may encourage blood cancer stem cells to die

Vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. 

Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.
“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of Perlmutter Cancer Center.
Changes in the genetic code, or mutations, that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.

Along with these diseases, new tests suggest that about 2.5 percent of all United States cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumours, say the authors.

The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context. These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.
The back-and-forth attachment and removal of methyl groups also fine tunes gene expression in stem cells, which can mature, specialize, and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection.

The enzyme studied in this report TET2, enables a change in the molecular structure, or oxidation, of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a countdown toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Dr. Neel.

To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.
Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.


Autora: Clinlabint
Fonte: Clinlabint
Sítio Online da Publicação: Clinlabint
Data de Publicação: 10/10/2017
Publicação Original: http://www.clinlabint.com/detail/clinical-laboratory/vitamin-c-may-encourage-blood-cancer-stem-cells-to-die/