Monday, 8 June 2015

Recovery of Sensory Function by Stem Cell Transplants

Recovery of Sensory Function by Stem Cell Transplants
Monday, 08 June 2015

New research from Uppsala University shows promising progress in the use of stem cells for treatment of spinal cord injury. The results, which are published in the scientific journal Scientific Reports, show that human stem cells that are transplanted to the injured spinal cord contribute to restoration of some sensory functions.

Traffic accidents and severe falls can cause ruptures of nerve fibres that enter/exit the spinal cord. Most commonly, these avulsion injuries affect the innervation of the arm and hand, and lead to paralysis, loss of sensation and cause chronic pain. Surgical interventions can help the patient regain some muscle function, but there is currently no treatment able to restore sensory functions. The reason for this is the emergence of a "barrier" at the junction between the ruptured nerve fibres and the spinal cord which prevents them from growing into the spinal cord and restore lost nerve connections.

In a new study the PhD students Jan Hoeber, Niclas König and Carl Trolle, working in Dr.Elena Kozlova's research group transplanted human stem cells to an avulsion injury in mice with the aim to restore a functional route for sensory information from peripheral tissues into the spinal cord.

The results show that the transplanted stem cells act as a "bridge" which allows injured sensory nerve fibres to grow into the spinal cord, rebuilds functional nerve connections, and thereby achieve long term restoration of major parts of the lost sensory functions. The transplanted stem cells differentiated to different types of cells with variable level of maturation, specific for the nervous system. No signs of tumour development or any functional abnormalities from the transplants were observed in the study, outcomes which are important in view of potential risks with transplantation of embryonic stem cells.

The results encourage further research on the use of stem cells for treatment of injury and disease in the spinal cord, and may contribute to the development of novel treatment strategies in these disorders.

Contact: Elena Kozlova

Reference:
Human embryonic stem cell-derived progenitors assist functional sensory regeneration after dorsal root avulsion injury
Hoeber J, Trolle C, König N, Du Z, Gallo A, Hermans E, Aldskogius H, Shortland P, Zheng, S-C, Deumens R, Kozlova EN. 
Scientific Reports 5, 08 June 2015, Article number: 10666, doi:10.1038/srep10666

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Thursday, 7 May 2015

Master Orchestrator of the Genome Is Discovered

Master Orchestrator of the Genome Is Discovered
Thursday, 07 May 2015

One of developmental biology’s most perplexing questions concerns what signals transform masses of undifferentiated cells into tremendously complex organisms, a process called ontogeny.

UB research suggests a new paradigm, visualized
in this diagram, for developmental global genome
programming by the nuclear FGFR1 protein.
New research by University at Buffalo scientists, published last week in PLOS ONE, provides evidence that it all begins with a single “master” growth factor receptor that regulates the entire genome.

“The finding provides a new level of understanding of the fundamental aspects of how organisms develop,” says senior author Michal K. Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences and senior author. He also directs the Stem Cell Engraftment and In Vivo Analysis Facility and the Stem Cell Culture and Training Facility at the Western New York Stem Cell Culture and Analysis Center at UB.

“Our research shows how a single growth factor receptor protein moves directly to the nucleus in order to program the entire genome,” he said.

Michal Stachowiak, PhD, Professor, Department
of Pathology and Anatomical Sciences. 
The research challenges a long-held supposition in biology that specific types of growth factors only functioned at a cell’s surface. For two decades, Stachowiak’s team has been intrigued by the possibility that growth factors function from within the nucleus, a point, he says, this current paper finally proves.

A more advanced understanding of how organisms form, based on this work, has the potential to significantly enhance the understanding and treatment of cancers, which result from uncontrolled development as well as congenital diseases, the researchers say. The new research also will contribute to the understanding of how stem cells work.

This work was conducted on mouse embryonic stem cells, not human cells.

Organizing ‘this cacophony of genes’
“We’ve known that the human body has almost 30,000 genes that must be controlled by thousands of transcription factors that bind to those genes,” Stachowiak said, “yet we didn’t understand how the activities of genes were coordinated so that they properly develop into an organism.”

“Now we think we have discovered what may be the most important player, which organizes this cacophony of genes into a symphony of biological development with logical pathways and circuits,” he said.

At the centre of the discovery is a single protein called nuclear Fibroblast Growth Factor Receptor 1 (nFGFR1).

“FGFR1 occupies a position at the top of the gene hierarchy that directs the development of multicellular animals,” said Stachowiak.

The FGFR1 gene is known to govern gastrulation, occurring in early development, where the three-layered embryonic structure forms. It also plays a major role in the development of the central and peripheral nervous systems and the development of the body’s major systems, including muscles and bones.

To study how nuclear FGFR1 worked, the UB team used genome-wide sequencing of mouse embryonic stem cells programmed to develop cells of the nervous system, with additional experiments in which nuclear FGFR1 was either introduced or blocked. The researchers found that the protein was responsible, either alone or with so-called partner nuclear receptors, for ensuring that embryonic stem cells develop into differentiated cells. By targeting thousands of genes, it controls the development of the major points of growth in the body (known as axes) as well as neuronal and muscle development.

The research shows that nuclear FGFR1 binds to promoters of genes that encode transcription factors, the proteins that control which genes are turned on or off in the genome.

“We found that this protein works as a kind of ‘orchestration factor,’ preferably targeting certain gene promoters and enhancers. The idea that a single protein could bind thousands of genes and then organize them into a hierarchy, that was unknown,” Stachowiak said.

“Nobody predicted it.”

Sequencing advances
The discovery that a single protein can exert such a global genomic function stems from recent advances in DNA sequencing technologies, which allow for the sequencing of a complex genome in just hours.

“NextGen DNA sequencing allows us to analyse millions of DNA sequences selected by the interacting protein,” Stachowiak said.

In the UB research, the DNA sequencing data were processed by the supercomputer at the university’s Center for Computational Research (CCR). Stachowiak and his colleagues then spent weeks aligning these data to the genome and conducting further analyses.

“We imposed nuclear FGFR1 on every little corner of genome,” he said.

“The computer spit out which genes are affected by nuclear FGFR1: it was an enormously complex network of genome activity.”

They found that the protein binds to genes that make neurons and muscles as well as to an important oncogene, TP63, which is involved in a number of common cancers.

Other studies in Stachowiak’s laboratory demonstrate that these interactions also take place in the human genome, controlling function and possibly underlying diseases like schizophrenia. Targeting of the nuclear FGFR1 allows for the reactivation of neural development in the adult brain in preclinical studies and thus, Stachowiak says, may offer unprecedented opportunity for regenerative medicine. Nuclear accumulation of nuclear FGFR1 may be altered in some cancer cells, and thus could become a focus in cancer therapy, he added.  

“This seminal discovery lends new perspectives to the origin, nature and treatment of a variety of human disease,” Stachowiak concluded.

Source: University at Buffalo, New York
Contact: Ellen Goldbaum

Reference:
Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1)
Christopher Terranova,Sridhar T. Narla, Yu-Wei Lee, Jonathan Bard, Abhirath Parikh, Ewa K. Stachowiak, Emmanuel S. Tzanakakis, Michael J. Buck, Barbara Birkaya, Michal K. Stachowiak
PLoS ONE 2015 10(4):e0123380, doi:10.1371/journal.pone.0123380
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New Stem Cell May Overcome Hurdles for Regenerative Medicine

Salk Institute scientists discover new type of stem cell that could potentially generate mature, functional tissues
Thursday, 07 May 2015

In this image, a novel type of human stem cell is
shown in green integrating and developing into
the surrounding cells of a nonviable mouse
embryo. Red indicates cells of endoderm lineage.
Endoderm cells can give rise to tissue that covers
organs from the digestive and respiratory
systems. The new stem cell, developed at the
Salk Institute, holds promise for one day growing
replacement functional cells and tissues. Credit:
Courtesy of the Salk Institute for Biological

Studies.
Scientists at the Salk Institute have discovered a novel type of pluripotent stem cell – cells capable of developing into any type of tissue – whose identity is tied to their location in a developing embryo. This contrasts with stem cells traditionally used in scientific study, which are characterized by their time-related stage of development.

In the paper, published May 6, 2015 in Nature, the scientists report using these new stem cells to develop the first reliable method for integrating human stem cells into nonviable mouse embryos in a laboratory dish in such a way that the human cells began to differentiate into early-stage tissues.

“The region-specific cells we found could provide tremendous advantages in the laboratory to study development, evolution and disease, and may offer avenues for generating novel therapies,” says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the paper and holder of Salk’s Roger Guillemin Chair.

The researchers dubbed this new class of cells “region-selective pluripotent stem cells,” or rsPSCs for short. The rsPSCs were easier to grow in the laboratory than conventional human pluripotent stem cells and offered advantages for large-scale production and gene editing (altering a cell’s DNA), both desirable features for cell replacement therapies.

Juan Carlos Izpisua Belmonte and Jun Wu
Credit: Courtesy of the Salk Institute for
Biological Studies.
To produce the cells, the Salk scientists developed a combination of chemical signals that directed human stem cells in a laboratory dish to become spatially oriented.

They then inserted the spatially oriented human stem cells (human rsPSCs) into specific regions of partially dissected mouse embryos and cultured them in a dish for 36 hours. Separately, they also inserted human stem cells cultured using conventional methods, so that they could compare existing techniques to their new technique.

While the human stem cells derived through conventional methods failed to integrate into the modified embryos, the human rsPSCs began to develop into early stage tissues. The cells in this region of an early embryo undergo dynamic changes to give rise to all cells, tissues and organs of the body. Indeed the human rsPSCs began the process of differentiating into the three major cell layers in early development, known as ectoderm, mesoderm and endoderm. The Salk researchers stopped the cells from differentiating further, but each germ layer was theoretically capable of giving rise to specific tissues and organs.

The new stem cell (green), developed at the Salk
Institute, holds promise for one day growing
replacement functional cells and tissues. Credit:
Courtesy of the Salk Institute for Biological

Studies.
Collaborating with the labs of Salk Professors Joseph Ecker and Alan Saghatelian, the Izpisua Belmonte team performed extensive characterization of the new cells and found rsPSCs showed distinct molecular and metabolic characteristics as well as novel epigenetic signatures – that is, patterns of chemical modifications to DNA that control which genes are turned on or off without changing the DNA sequence.

“The region selective-state of these stem cells is entirely novel for laboratory-cultured stem cells and offers important insight into how human stem cells might be differentiated into derivatives that give rise to a wide range of tissues and organs,” says Jun Wu, a postdoctoral researcher in Izpisua Belmonte’s lab and first author of the new paper.

“Not only do we need to consider the timing, but also the spatial characteristics of the stem cells. Understanding both aspects of a stem cell’s identity could be crucial to generate functional and mature cell types for regenerative medicine.”

Contact: Salk Communications

Reference:
An alternative pluripotent state confers interspecies chimaeric competency
Authors: Jun Wu, Daiji Okamura, Mo Li, Keiichiro Suzuki, Chongyuan Luo,Li Ma, Yupeng He, Zhongwei Li, Chris Benner, Isao Tamura, Marie N. Krause, Joseph R. Nery, Tingting Du, Zhuzhu Zhang, Tomoaki Hishida, Yuta Takahashi, Emi Aizawa, Na Young Kim, Jeronimo Lajara, Pedro Guillen, Josep M. Campistol, Concepcion Rodriguez Esteban, Pablo J. Ross, Alan Saghatelian, Bing Ren, Joseph R. Ecker and Juan Carlos Izpisua Belmonte
Nature, 06 May 2015, doi:10.1038/nature14413
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