Thursday, August 28, 2014

Fully Functional Organ from Scratch in a Living Animal by Transplanting Cells

Fully functional immune organ grown in mice from lab-created cells


Scientists have for the first time grown a complex, fully functional organ from scratch in a living animal by transplanting cells that were originally created in a laboratory. The advance could in future aid the development of ‘lab-grown’ replacement organs.




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Fibroblasts transformed into induced thymic epithelial cells (iTEC) in vitro (left, iTEC in green). iTEC transplanted onto the mouse kidney form an organised and functional mini-thymus (right, kidney cells in pink, thymus cells in dark blue)


Researchers from the MRC Centre for Regenerative Medicine, at the University of Edinburgh, took cells called fibroblasts from a mouse embryo and converted them directly into a completely unrelated type of cell - specialised thymus cells- using a technique called ‘reprogramming’. When mixed with other thymus cell types and transplanted into mice, these cells formed a replacement organ that had the same structure, complexity and function as a healthy native adult thymus. The reprogrammed cells were also capable of producing T cells - a type of white blood cell important for fighting infection - in the lab.


The researchers hope that with further refinement their lab-made cells could form the basis of a readily available thymus transplant treatment for people with a weakened immune system. They may also enable the production of patient-matched T cells. The research is published today in the journal Nature Cell Biology.

The thymus, located near the heart, is a vital organ of the immune system. It produces T cells, which guard against disease by scanning the body for malfunctioning cells and infections. When they detect a problem, they mount a coordinated immune response that tries to eliminate harmful cells, such as cancer, or pathogens like bacteria and viruses.

People without a fully functioning thymus can’t make enough T cells and as a result are very vulnerable to infections. This can be a particular problem for some patients who need a bone marrow transplant (for example to treat leukaemia), as a functioning thymus is needed to rebuild the immune system once the transplant has been received. The problem can also affect children; around one in 4,000 babies born each year in the UK have a malfunctioning or completely absent thymus (due to conditions such as DiGeorge syndrome).

Thymus disorders can sometimes be treated with infusions of extra immune cells, or transplantation of a thymus organ soon after birth, but both are limited by a lack of donors and problems matching tissue to the recipient.

Being able to create a complete transplantable thymus from cells in a lab would be a huge step forward in treating such conditions. And while several studies have shown it is possible to produce collections of distinct cell types in a dish, such as heart or liver cells, scientists haven’t yet been able to grow a fully intact organ from cells created outside the body.

Professor Clare Blackburn from the MRC Centre for Regenerative Medicine at the University of Edinburgh, who led the research, said:

“The ability to grow replacement organs from cells in the lab is one of the ‘holy grails’ in regenerative medicine. But the size and complexity of lab-grown organs has so far been limited. By directly reprogramming cells we’ve managed to produce an artificial cell type that, when transplanted, can form a fully organised and functional organ. This is an important first step towards the goal of generating a clinically useful artificial thymus in the lab.”

The researchers carried out their study using cells (fibroblasts) taken from mouse embryos. By increasing levels of a protein called FOXN1, which guides development of the thymus during normal organ development in the embryo, they were able to directly reprogramme these cells to become a type of thymus cell called thymic epithelial cells. These are the cells that provide the specialist functions of the thymus, enabling it to make T cells.

The induced thymic epithelial cells (or iTEC) were then combined with other thymus cells (to support their development) and grafted onto the kidneys of genetically identical mice. After four weeks, the cells had produced well-formed organs with the same structure as a healthy thymus, with clearly defined regions (known as the cortex and medulla). The iTEC cells were also able to produce different types of T cells from immature blood cells in the lab.

Dr Rob Buckle, Head of Regenerative Medicine at the MRC, said:

“Growing ‘replacement parts’ for damaged tissue could remove the need to transplant whole organs from one person to another, which has many drawbacks – not least a critical lack of donors. This research is an exciting early step towards that goal, and a convincing demonstration of the potential power of direct reprogramming technology, by which once cell type is converted to another. However, much more work will be needed before this process can be reproduced in the lab environment, and in a safe and tightly controlled way suitable for use in humans.”

The study was funded by Leukaemia & Lymphoma Research, Darwin Trust of Edinburgh, the MRC and the European Union Seventh Framework Programme.

News Release Source : Fully functional immune organ grown in mice from lab-created cells

Successfully Established a Three-Dimensional Culture Model of the Developing Brain

BRAINS ON DEMAND


August 28, 2013


Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of NATURE allows pluripotent stem cells to develop into cerebral organoids – or "mini brains" – that consist of several discrete brain regions. Instead of using so-called patterning growth factors to achieve this, scientists at the renowned Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the "mini brains", the scientists were also able to model the development of a human neuronal disorder and identify its origin – opening up routes to long hoped-for model systems of the human brain.




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The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain’s development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. J├╝rgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has changed just that.



Brain Size Matters


Starting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: "We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed."


Already after 15 – 20 days, so-called "cerebral organoids" formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 – 30 days, defined brain regions, including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.


Microcephaly in Mini Brains

The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease. Knoblich’s group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size. Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size. Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder.


"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," explains Dr. Madeline A. Lancaster, team member and first author of the publication. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development."


 Original publication Nature: M. A. Lancaster, M. Renner, C.-A. Martin, D. Wenzel, L. S. Bicknell, M. E. Hurles, T. Homfray, J. S. Penninger, A. P. Jackson & J. A. Knoblich. Cerebral organoids derived from pluripotent stem cells model human brain development and microcephaly. doi: 10.1038/nature12517

News Release Source :  BRAINS ON DEMAND