Growing Human Esophagus Tissue from Human Cells

Tracy Grikscheit of the Saban Research Institute of Children’s Hospital Los Angeles and her colleagues have successfully grown a tissue engineered esophagus on a relatively simple biodegradable scaffold after seeding it with the appropriate stem and progenitor cells.

Progenitor cells have the ability to differentiate into specific cell types and can migrate to a particular target tissue. Their differentiation potential depends on the parent cell type from which they descended and their “niche” or local surroundings. The scaffold upon which these cells were seeded is composed of a simple polymer, but interestingly, several different combinations of cell types were able to generate a replacement organ that worked well when transplanted into laboratory mice.

“We found that multiple combinations of cell populations allowed subsequent formation of engineered tissue. Different progressive cells can find the right “partner” cell in order to grow into specific esophageal cell types; such as epithelium, muscle or nerve cells, and without the need for exogenous growth factors. This means that successful tissue engineering of the esophagus is simpler than we previously thought,” said Grikscheit.

Videos published the paper show a network of muscle cells properly wired with nerves that properly self-organizes whose muscles spontaneously contract.  Such structures are called an esophageal organoid unit (EOU) in culture. Spontaneous contraction is observed within these EOUs.

This study could be the impetus for clinical procedures that can treat children born with portions of their esophagus missing. Since the esophagus carries liquids and food to the stomach from the mouth, it is a vitally important part of the body.

This protocol, could also be applied to patients who have suffered from esophageal cancer and had to have their esophagus removed. Esophageal cancer is one of the fastest growing types of cancer in the United States to date. Alternatively, people who have accidentally swallowed caustic liquids may also benefit from this type of esophageal repair.

This simple scaffold made of a polyglycolic acid/poly-L-lactic acid and coated with the protein collagen is inexpensive and versatile and completely sufficient for the growth of tissue-engineered esophagi from human cells, according to this study. When established in culture, this system can also serve as a model system to study the cell dynamics and physiology of the esophagus.

A deeper understanding of how esophageal cells behave in response to injury and how various donor cells could potentially expand the pool of potential donor cells for engineered tissue.

Even though this technique has only been tested in animals to date, fine-tuning of this technique might very well ready it for clinical trials in the future.

How Neural Stem Cells Become Neurons and Glia

How do neural stem cells differentiate into neurons or glia? A new paper from researchers at the University of California, Los Angeles (UCLA) seeks to explain this very phenomenon.

Neurons serve as the conductive cells of the nervous system. They transmit electrochemical signals from one neuron to another and provide signals to muscles, glands, and so on. They are responsible for consciousness, thought, learning and memory, and personality.

Despite their immense utility, neurons are not the only cells in the nervous system. Glial cells or just glia support neurons, hold them in place, and supply neurons with oxygen and nutrients and protect them from pathogens.

Glial Cells

When mouse neural stem cells were grown in culture, Wange Lu, associate professor of biochemistry and molecular biology at the Keck School of Medicine, and his colleagues came upon a protein called SMEK1 that promotes the differentiation of neural stem and progenitor cells. SMEK1 also keeps neural stem cells in check by preventing them from dividing uncontrollably.

When Lu and others took a more detailed look at the role of SMEK1, they discovered that it does not work alone, but in concert with a protein called Protein Phosphatase 4 (PP4) to suppress the function of a third protein called PAR3. PAR3 discourages the birth of new neurons (neurogenesis), and PAR3 inhibition leads to the differentiation of neural stem progenitor cells into neurons and glia.

“These studies reveal the mechanisms of how the brain keeps the balance of stem cells and neurons when the brain is formed,” said Wange. “If this process goes wrong, it leads to cancer, or mental retardation or other neurological diseases.”

Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step towards co-opting the therapeutic potential of these cells. This could offer new treatments for patients who suffer from Alzheimer’s, Parkinson’s and many other currently incurable diseases.

This work is interesting. It was published in Cell Reports 5, 593–600, November 14, 2013. My only criticism of some of the thinking in this paper is that neural stem cell lines are usually made from aborted fetuses. I realize that some of these neural stem cell lines come from medical abortions in which the baby had already died, but many of them come from aborted babies. If we are going to use neural stem cells for therapeutic purposes, then we should make them from induced pluripotent stem cells and take them from aborted babies.

New 3D Method Used to Grow Miniature Pancreas

Researchers from the University of Copenhagen, in collaboration with an international team of investigators, have successfully developed an innovative three-dimensional method to grow miniature pancreas from progenitor cells. The future goal of this research is to utilize this model system to fight against diabetes. This research was recently published in the journal Development.

The new method allows the cell material from mice to grow vividly in picturesque tree-like structures.
The new method allows the cell material from mice to grow vividly in picturesque tree-like structures.

The new method takes cell material from mice and grows them in vividly picturesque tree-like structures.  The cells used were mouse embryonic pancreatic progenitors, and they were grown in a compound called Matrigel with accompanying cocktails of growth factors.  In vitro maintenance and expansion of these pancreatic progenitors requires active Notch and FGF signaling, and therefore, this culture system recapitulated the in vivo conditions that give rise to the pancreas in the embryo.

Professor Anne Grapin-Botton and her team at the Danish Stem Cell Centre, in collaboration with colleagues from the Ecole Polytechnique Fédérale de Lausanne in Switzerland, have developed a three-dimensional culture method that takes pancreatic cells and vigorously expands them. This new method allows the cell material from mice to grow vividly into several distinct picturesque, tree-like structures. The method offers tremendous long-term potential in producing miniature human pancreas from human stem cells. Human miniature pancreas organoids would be valuable as models to test new drugs fast and effectively, without the use of animal models.

“The new method allows the cell material to take a three-dimensional shape enabling them to multiply more freely. It’s like a plant where you use effective fertilizer, think of the laboratory like a garden and the scientist being the gardener,” says Anne Grapin-Botton.

In culture, pancreatic cells neither thrive nor develop if they are alone. A minimum of four pancreatic cells, growing close together is required for these cells to undergo organoid development.

“We found that the cells of the pancreas develop better in a gel in three-dimensions than when they are attached and flattened at the bottom of a culture plate. Under optimal conditions, the initial clusters of a few cells have proliferated into 40,000 cells within a week. After growing a lot, they transform into cells that make either digestive enzymes or hormones like insulin and they self-organize into branched pancreatic organoids that are amazingly similar to the pancreas,” adds Anne Grapin-Botton.

The scientists used this system to discover that the cells of the pancreas are sensitive to their physical environment, and are influenced by such seemingly insignificant factors as the stiffness of the gel and contact with other cells.

An effective cellular therapy for diabetes is dependent on the production of sufficient quantities of functional beta-cells. Recent studies have enabled the production of pancreatic precursors but efforts to expand these cells and differentiate them into insulin-producing beta-cells have proved a challenge.

“We think this is an important step towards the production of cells for diabetes therapy, both to produce mini-organs for drug testing and insulin-producing cells as spare parts. We show that the pancreatic cells care not only about how you feed them but need to be grown in the right physical environment. We are now trying to adapt this method to human stem cells,” adds Anne Grapin-Botton.

Newly Identified Stem Cell Population In Skin Is Responsible for Wound Healing

BRUSSELS, Belgium, September 3, 2012 – Skin researchers from the Universitй Libre de Bruxelles, Belgium have discovered a new stem cell population in skin that is responsible for tissue repair.

Our skin protects our bodies from the environment and its toxins, hard knocks, and extremes of temperature, pressure and so on. Consequently, the skin is subject to constant replacement and dead cells are sloughed off and replaced throughout our lifetimes.

However, the number of cells generated by the skin must exactly replace those that are lost. Different theories have been proposed to explain how this delicate balance is maintained.

In this new study, Prof. Cйdric Blanpain and his colleagues have collaborated with Prof. Benjamin Simons at the University of Cambridge, U.K. to show that a new population of stem cells in the skin give rise to a population of progenitor cells that are involved in the daily maintenance of the upper layers of the skin (epidermis). In fact, these stem cells are the major contributor during wound healing.

Blanpain and others used a novel genetic lineage tracing protocol to fluorescently mark two distinct skin cell populations, and follow their survival and contribution to the maintenance of the epidermis over time. These labeling experiments demonstrated the existence of two types of dividing cells. One cell population showed very long-term survival potential while the other population is progressively lost over time.

With Benjamin D. Simons, Blanpain and his lab devised a mathematical model of their lineage tracing analysis. The model suggested that skin, particularly the epidermis, contains a population of stem cells that divide very slowly that give rise to very fast dividing progenitor cells that ensure the daily maintenance of the skin epidermis. Cell proliferation patterns confirmed the existence of slow cycling stem cells. Furthermore, gene profiling experiments showed that the stem and the progenitor cells are characterized by distinct patterns of gene expression.

By assessing the contribution of these two cell populations during wound healing, they showed that only the skin stem cells were capable of extensive tissue regeneration and undergo major expansion during this repair process. The progenitors, on the other hand, did not expand significantly, but provided a short-lived contribution to the wound healing response.

These data resolve a long-standing debate regarding the cell populations that contribute to wound healing in the skin. Apparently, these epidermal stem cells are the main players during wound healing.

“It was amazing to see these long trails of cells coming from a single stem cell located at a very long distance from the wound to repair the epidermis,” said Dr.  Blanpain, who was the senior author of the study.

Thus the slow-dividing stem cells promote tissue repair and more the more rapidly dividing progenitors ensure the daily maintenance of the epidermis.

Interestingly, similar populations of slow cycling stem cells that can be rapidly mobilized in case of sudden need have been observed in other tissues, such as the blood, muscle and hair follicle. The division between rapidly cycling progenitors and slow cycling stem cells seems to be relatively conserved across the different tissues.

Of course, these findings may have important implications in regenerative medicine; in particular for skin repair in severely burnt patients or in chronic wounds.