Stem Cell Transplants Help Kidney Damage

Stem Cell Transplants Help Kidney Damage
Tuesday, 15 February 2011

Transplanting autologous renal progenitor cells (RPCs), (kidney stem cells derived from self-donors), into rat models with kidney damage from pyelonephritis - a type of urinary infection that has reached the kidney - has been found to improve kidney structure and function.

The study, authored by a research team from the Tehran University of Medical Sciences, is published in the current issue of Cell Medicine.

"Advancements in stem cell therapies and tissue engineering hold great promise for regenerative nephrology," said Dr. Abdol-Mohammad Kajbafzadeh, corresponding author.

"Our RPC transplant study demonstrated benefits for pyelonephritis, a disease characterized by severe inflammation, renal function impairment and eventual scarring, and which remains a major cause of end-stage-renal disease worldwide."

The researchers divided 27 rats into three groups, two of which were modelled with an induced pyelonephritis in their right kidneys, while the third group did not have induced disease. RPCs were obtained from the diseased animals' left kidneys and injected into the right kidney six weeks later. Two weeks after injection, tubular atrophy was reduced. After four weeks, fibrosis was reduced and after sixty days, right renal tissue integrity was "significantly improved."

"We propose that kidney augmentation was mainly due to functional tissue regeneration following cellular transplantation," said Dr. Kajbafzadeh.

"Kidney-specific stem/progenitor cells might be the most appropriate candidates for transplantation because of their inherent organ-specific differentiation and their capacity to modulate tissue remodelling in chronic nephropathies."

The researchers concluded that because renal fibrosis is a common and ultimate pathway leading to end-stage renal disease, amelioration of fibrosis might be of major clinical relevance.

"Transplanting RPCs showed the potential for partial augmentation of kidney structure and function in pyelonephritis," said Dr. Kajbafzadeh.

"This is one of the first studies to demonstrate improved renal function after cell transplantation. The translation of this study into larger clinical models will be very relevant to validate the success of this small animal study." said Dr. Amit Patel, Section Editor Cell Medicine, Associate Professor of Surgery, University of Utah.

Source: Florida Science Communications
Contact: Randolph Fillmore

Reference:
Autografting of Renal Progenitor Cells Ameliorates Kidney Damage in Experimental Model of Pyelonephritis
Kajbafzadeh, A-M.; Elmi, A.; Talab, S. S.; Sadeghi, Z.; Emami, H.; Sotoudeh, M.
Cell Med. 1(3): 115-122; 2010
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ZenMaster

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Gene Regulation Mechanism Unique to Primates Discovered

Study finds long-known, but little-understood DNA elements serve important purpose
Thursday, 10 February 2011

Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. Though the human genome – all the genes that an individual possesses – was sequenced 10 years ago, greater understanding of how genes function and are regulated is needed to make advances in medicine, including changing the way we diagnose, treat and prevent a wide range of diseases.

"It's extremely valuable that we've sequenced a large bulk of the human genome, but sequence without function doesn't get us very far, which is why our finding is so important," said Lynne E. Maquat, Ph.D., lead author of the new study published today in the journal Nature.

When our genes go awry, many diseases, such as cancer, Alzheimer's and cystic fibrosis can result. The study introduces a unique regulatory mechanism that could prove to be a valuable treatment target as researchers seek to manipulate gene expression – the conversion of genetic information into proteins that make up the body and perform most life functions – to improve human health.

The newly identified mechanism involves Alu elements, repetitive DNA elements that spread throughout the genome as primates evolved. While scientists have known about the existence of Alu elements for many years, their function, if any, was largely unknown.

Maquat discovered that Alu elements team up with molecules called long noncoding RNAs (lncRNAs) to regulate protein production. They do this by ensuring messenger RNAs (mRNAs), which take genetic instructions from DNA and use it to create proteins, stay on track and create the right number of proteins. If left unchecked, protein production can spiral out of control, leading to the proliferation or multiplication of cells, which is characteristic of diseases such as cancer.

"Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we've shown that they actually have important roles in regulating protein production," said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center.

The expression of genes that call for the development of proteins involves numerous steps, all of which are required to occur in a precise order to achieve the appropriate timing and amount of protein production. Each of these steps is regulated, and the pathway discovered is one of only a few pathways known to regulate mRNAs directly in the midst of the protein production process.

Regulating mRNAs is one of several ways cells control gene expression, and researchers from institutions and companies around the world are honing in on this regulatory landscape in search of new ways to manage and treat disease.

"This new mechanism is really a surprise. We continue to be amazed by all the different ways mRNAs can be regulated," according to Maquat.

Maquat and the study's first author, Chenguang Gong, a graduate student in the Department of Biochemistry and Biophysics at the Medical Center, found that long noncoding RNAs and Alu elements work together to trigger a process known as SMD (Staufen 1-mediated mRNA decay). SMD conditionally destroys mRNAs after they orchestrate the production of a certain amount of proteins, preventing the creation of excessive, unwanted proteins in the body that can disrupt normal processes and initiate disease.

Specifically, long noncoding RNAs and Alu elements recruit the protein Staufen-1 to bind to numerous mRNAs. Once an mRNA finishes directing a round of protein production, Staufen-1 works with another regulatory protein previously identified by Maquat, UPF1, to initiate the degradation or decay of the mRNA so that it cannot create any more proteins.

While the research fills in a piece of the puzzle as to how our genes operate, it also accentuates the overwhelming complexity of how our DNA shapes us and the many known and unknown players involved. Maquat and Gong plan on exploring the newly identified pathway in future research.

Source: University of Rochester Medical Center
Contact: Emily Boynton

Reference:
lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements
Chenguang Gong & Lynne E. Maquat
Nature Vol. 470, 284–288, (10 February 2011), doi:10.1038/nature09701
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ZenMaster

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Cell Reprogramming Leaves a 'Footprint' Behind

Cell Reprogramming Leaves a 'Footprint' Behind
Wednesday, 09 February 2011

Reprogramming adult cells to recapture their youthful "can-do-it-all" attitude appears to leave an indelible mark, found researchers at the Salk Institute for Biological Studies. When the team, led by Joseph Ecker, PhD., a professor in the Genomic Analysis Laboratory, scoured the epigenomes of so-called induced pluripotent stem cells base by base, they found a consistent pattern of reprogramming errors.

What's more, these incompletely or inadequately reprogrammed hotspots are maintained when iPS cells are differentiated into a more specialized cell type, providing what the researchers dubbed an iPS cell-specific signature.

"We can tell by looking at these hotspots whether a cell is an iPS cell or an embryonic stem cell," says Ecker.

"But we don't know yet what it means for their self-renewal or differentiation potential."

Their findings, published in the February 3, 2011, issue of Nature, confirm that iPS cells, which by all appearances look and act like embryonic stem cells, differ in certain aspects from their embryonic cousins, emphasizing that further research will be necessary before they can rightfully take embryonic stem cells' place.


The reprogramming process leaves

indelible marks in the methylation profile

of induced pluripotent stem cells.

Credit: Courtesy of Dr. Ryan Lister, Salk

Institute for Biological Studies.

The fact that reprogramming of somatic (body) cells does not pose the same ethical quandaries as working with stem cells isolated from embryos prompted scientists to develop iPS technology for human cells that are just as potent as human embryonic stem cells, with the hope that one day, iPS cell technology can be applied to regenerative medicine.
However, before cells derived from iPS cells can be used to repair tissue damaged through disease or injury, some remaining questions have to be solved.

"Embryonic stem cells are considered the gold standard for pluripotency," says Ecker.

"So we need to know whether — and if so, how — iPS cells differ from ES cells."

The reprogramming process, which turns back the clock and endows fully differentiated cells with pluripotent potential, is not a genetic transformation but an epigenomic one. The epigenome is what differentiates a fibroblast from a hepatocyte and a stem cell from a fully differentiated cell. With a few exceptions, every cell in our body contains the same genome, but epigenomic marks — tiny tags atop DNA that can tell your genes to turn on or off, to speak up or speak softly — determine a cell's gene expression profile and hence its fate.

While others have compared genomic bits and pieces between iPS and embryonic stem cells — and found small differences — the Salk researchers and their collaborators at the University of Wisconsin and the University of California, San Diego, set their sights higher.

They scrutinized whole-genome DNA methylation profiles — methylation is one the best-studied and most important epigenetic tags — at single-base resolution in five iPS cell lines, along with the methylomes of embryonic stem cells and somatic cells and differentiated iPS cells and differentiated embryonic stem cells.

Reprogramming induces a remarkable wholesale reconfiguration of the DNA methylation pattern throughout the genome, returning partially methylated domains to a fully methylated state; reinstating so-called non-CG methylation; and reprogramming most un-methylated and methylated CG islands, which play a crucial role in regulation gene activity, to an embryonic stem cell-like state.

"Overall, this process results in an iPS cell methylation pattern that's very similar to that of embryonic stem cells," says postdoctoral researcher and co-first author Ryan Lister.

"But when we started to dig deeper, we discovered significant differences."

Their experiments revealed considerable variability between iPS cell lines, including a "memory" of their tissue of origin.

"Some marks carry over," explains Ecker.

"If iPS cells were derived from adipose tissue, we can see that they ‘remember’ some methylation marks from being a fat cell."

Furthermore, new methylation patterns not found in either embryonic stem cells or the tissues of origin were identified in the iPS cells, and many of the regions showing epigenomic changes were disrupted in all iPS lines studied.

But regardless of their individual history, iPS cells showed a common defect — hotspots near telomeres and centromeres that proved resistant to reprogramming. Averaging more than one million bases in length, these hotspots failed to acquire the non-CG methylation typical of embryonic stem cells.

"These regions are really signatures," explains postdoctoral researcher and co-first author Mattia Pelizzola.

"They are shared in iPS cells derived from different parental cells, by different research groups and using different methodologies. Moreover, these regions coincide with specific modifications of histones — proteins that are important to determine the accessibility and the activity of genomic regions — and the genes contained within these regions are less expressed."

However, when the researchers zoomed in closer, they found that the opposite held true for CG islands, short stretches of CG-rich DNA sequences that are typically found in the proximity of genes, where they may regulate gene activity.

"The consequence is that some genes within these areas seem to be silenced by the altered CG island methylation patterns in the iPS cells," says Lister.

"Conceivably, these changes could limit the potential fate of the iPS cells."

To gain a better understanding of the implications, they looked again at these regions after differentiating embryonic stem cells and iPS cells into trophoblasts, a standard cell differentiation assay. A subset of iPS cell-specific silencing marks was transmitted to differentiated cells at high frequency.

"They are not easily removed," says Lister, "and could be used as a diagnostic marker for incomplete reprogramming."

Adds Ecker: "Now that we know that these regions exist, we want to understand why these regions can't be reprogrammed to a more ES cell-like state."

Source: Salk Institute
Contact: Gina Kirchweger

Reference:
Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells
Ryan Lister, Mattia Pelizzola, Yasuyuki S. Kida, R. David Hawkins, Joseph R. Nery, Gary Hon, Jessica Antosiewicz-Bourget, Ronan O’Malley, Rosa Castanon, Sarit Klugman, Michael Downes, Ruth Yu, Ron Stewart, Bing Ren, James A. Thomson, Ronald M. Evans, & Joseph R. Ecker
Nature, 02 February 2011, doi:10.1038/nature09798
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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