Stories about: regenerative medicine

Biological ‘programmers’ crack new code in stem cells

Stem cell colony Wyss Institute James Collins George Daley complexity
Researchers discovered many small nuances in pluripotency states of stem cells by subjecting the cells to various perturbations and then analyzing each individual cell to observe all the different reactions to developmental cues within a stem cell colony. (Credit: Wyss Institute at Harvard University)

Stem cells offer great potential in biomedical engineering because they’re pluripotent—meaning they can multiply indefinitely and develop into any of the hundreds of different kinds of cells and tissues in the body. But in trying to tap these cells’ creative potential, it has so far been hard to pinpoint the precise biological mechanisms and genetic makeups that dictate how stem cells diverge on the path to development.

Part of the challenge, according to James Collins, PhD, a core faculty member at the Wyss Institute for Biologically Inspired Engineering, is that not all stem cells are created the same. “Stem cell colonies contain much variability between individual cells. This has been considered somewhat problematic for developing predictive approaches in stem cell engineering,” he says.

But now, Collins and Boston Children’s Hospital’s George Q. Daley, MD, PhD, have used a new, very sensitive single-cell genetic profiling method to reveal how the variability in pluripotent stem cells runs way deeper than we thought.

While at first glimmer, it could appear this would make predictive stem cell engineering more difficult, it might actually present an opportunity to exert even more programmable control over stem cell differentiation and development than was originally envisioned. “What was previously considered problematic variability could actually be beneficial to our ability to precisely control stem cells,” says Collins.

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Modeling pain in a dish: Nociceptors made from skin recreate pain physiology

Pain in a dish nociceptors

Chronic pain, affecting tens of millions of Americans alone, is debilitating and demoralizing. It has many causes, and in the worst cases, people become “hypersensitized”—their nervous systems fire off pain signals in response to very minor triggers.

There are no good medications to calm these signals, in part because the subjectivity of pain makes it difficult to study, and in part because there haven’t been good research models. Drugs have been tested in animal models and “off the shelf” cell lines, some of them engineered to carry target molecules (such as the ion channels that trigger pain signals). Drug candidates emerging from these studies initially looked promising but haven’t panned out in clinical testing.

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Stem cell medicine gets a “roadmap” and a quality assurance tool

cell fate map Boston subway
Credit: Samantha Morris, PhD, Boston Children’s Hospital

If you’ve lost your way on the Boston subway, you need only consult a map to find the best route to your destination. Now stem cell engineers have a similar map to guide the making of cells and tissues for disease modeling, drug testing and regenerative medicine. It’s a computer algorithm known as CellNet.

As in this map on the cover of Cell, a cell has many possible destinations or “fates,” and can arrive at them through three main stem cell engineering methods:

reprogramming (dialing a specialized cell, such as a skin cell, back to a stem-like state with full tissue-making potential)
differentiation (pushing a stem cell to become a particular cell type, such as a blood cell)
direct conversion (changing one kind of specialized cell to another kind)

Freely available on the Internet, CellNet provides clues to which methods of cellular engineering are most effective—and acts as a much-needed quality control tool.

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Turning heart growth on and off: MicroRNAs could point to new treatments

In mice, boosting amounts of a microRNA family called miR-17-92 led to dramatic enlargements of embryonic and postnatal hearts, with thicker ventricle walls.

 

Challenging accepted wisdom about the heart, Boston Children’s Hospital cardiologist Bernhard Kühn, MD, recently showed that infants, children and adolescents are capable of generating new heart muscle cells, or cardiomyocytes. That work raised the possibility that scientists could stimulate regeneration to repair injured hearts.

Now, we have a potential therapeutic target to accomplish this: a family of microRNAs called miR-17-92 that regulates cardiomyocyte proliferation. In Circulation Research earlier this month, a team led by Kühn’s research colleague Da-Zhi Wang, PhD, demonstrates its potential.

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A regenerative approach to heart failure in children?

A heart muscle cell from an 8-year-old beginning the process of mitosis: The cell nucleus is preparing to divide. (Courtesy Bernhard Kühn)

For more than 100 years, people have been debating whether human hearts can grow after birth by generating new contractile muscle cells, known as cardiomyocytes. Recently, Bernhard Kühn, MD, at Boston Children’s Hospital and his colleagues added fuel to the debate—and hope for regenerative therapies for diseased hearts—with their findings that infants, children and adolescents are indeed capable of generating new cardiomyocytes.

Research in the 1930s and 1940s suggested that cardiomyocyte division may continue after birth, and recent investigations in zebrafish and newborn mice presented the possibility that some young animals can regenerate heart muscle through muscle cell division. Still, for many years, the accepted dogma among physicians and researchers was that human hearts grow after birth only through existing cells growing larger.

“This is a very sticky subject in cardiology,” says Kühn. Not only do long-held scientific beliefs die hard, but the ability to directly study heart cell growth in humans has been limited. “Healthy human hearts are hard to come by,” he says.

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Epigenetic enzymes thicken the iPS cell reprogramming plot

Manipulating the enzymes that turn genes on and off could help make the process of reprogramming cells into iPS cells a lot more efficient and safer.

There are several ways to reprogram skin cells into induced pluripotent stem (iPS) cells – cells that behave like embryonic stem cells, and which could help better understand the genetic basis of and develop new treatments for different diseases.

The major methods scientists use now include using viruses to deliver reprogramming genes or using RNAs to produce the necessary proteins without the genes. Different methods have different advantages and disadvantages, and some are more efficient than others.

What’s common across all of the methods is that they rely on four proteins to turn back the cellular clock – c-Myc, Klf4, Oct4, and Sox2. Less understood is whether enzymes that modify chromatin (the DNA-plus-protein package that constitutes our genome) play any role in the reprogramming process. These enzymes manage and control the cell’s epigenetic code – the layer of control that helps cells fine-tune gene expression by adding and removing small chemical tags to genes and proteins.

“During iPS reprogramming, a cell’s epigenetic code gets completely rewritten,” says George Q. Daley, director of the Stem Cell Transplantation Program at Children’s Hospital Boston. “But how the cell’s epigenetic enzymes influence the reprogramming process has been a mystery.”

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Stem cell experiments in genetic blood diseases

The green tips of these chromosomes are telomeres, whose length is a measure of cellular "aging" and determines how many times a cell can divide.

In a roomful of kids’ cancer specialists, like those listening to the keynote speech by George Daley, closing an international pediatric oncology meeting in Boston, the Myc gene is better known as a mutated weapon of mass destruction.

But this driver of cancer growth is also part of a four-gene cocktail that can reprogram an adult skin cell back into an embryonic-like stem cell that holds great therapeutic potential.

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iPS cells: A promising new platform for drug discovery

Within five years, likely well before we start treating patients with their own genetically corrected stem cells created from induced pluripotent stem cells, I am expecting to see new drugs discovered using iPS cells enter the clinical pipeline.

It’s only been two years since three labs (ours included) created the first human iPS cells through genetic reprogramming of skin cells.

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