How do Zebrafish grow ears? It’s quite transparent

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Zebrafish

One of the hopes of regenerative medicine is that one day we will be able to use stem cells to regrow damaged organs, avoiding the need for a transplant. It’s a fascinating idea, supported in part by the ability of some creatures, such as Axolotls and salamanders, to regrow parts of their anatomy that they have lost.

But there’s quite a leap from a lizard to a human and bridging that gap is proving far from easy. One of the problems is simply understanding how cells know what to do to form the correct shape for the organ. Even something as relatively simple as an ear is incredibly complex.

However, researchers at Harvard Medical School have discovered a way to replicate how cells form into flexible sheets, so they can be folded into the delicate shape of tubes in the inner ear. They did this by studying Zebrafish. Why? In an article in Genetic Engineering and Biology News Dr. Akankshi Munjal, PhD, first author of the paper, said the reason was simple.

Akankshi Munjal, PhD, first author of the paper; Photo courtesy Harvard Medical School

“Zebrafish are transparent, so we just stick them under a microscope and look at this entire process from a single cell to a larva that can swim and has all its parts.”

Because they could watch the Zebrafish develop in real time, they were able to observe what the cells were doing at any point simply by looking at the fish under a microscope. Another advantage is that in Zebrafish the semicircular canals of the inner ear – tubes that help them maintain balance and orient themselves – form close to the surface, making it even easier to see what was going on.

In the study, published in the journal Cell, the researchers say it appears that a combination of pressure generated by hyaluronic acid, which acts as a cushion and lubricant between tissues, and molecular tethers between cells help direct flat sheets of cells into tubes and other shapes.

Dr. Sean Megason, one of the authors of the paper, said that knowing the mechanism at work is really important. “Right now tissue engineers are trying to build tissues without knowing how cells normally do this during embryonic development. We want to define these rules such that cells can be programmed to assemble into any desired pattern and shape. This work shows a new way in which cells can generate force to bend tissues into the right shape.”

The researchers say if they can understand how cells work together to create these complex shapes they may be better able to replicate that process in the lab, and grow ears, parts of ears or even other organs for people.

An Atlas of the Human Heart that May Guide Development of New Therapies

By Lisa Kadyk, PhD. CIRM Senior Science Officer

Illustration of a man’s heart – Courtesy Science Photo

I love maps; I still have auto club maps of various parts of the country in my car.  But, to tell the truth, those maps just don’t have as much information as I can get by typing in an address on my cell phone.  Technological advances in global positioning systems, cellular service, data gathering and storage, etc. have made my beloved paper maps a bit of a relic.  

Similarly, technological advances have enabled scientists to begin making maps of human tissues and organs at a level of detail that was previously unimaginable.  Hundreds of thousands of single cells can be profiled in parallel, examining expression of RNA and proteins.  These data, in combination with new three-dimensional spatial analysis techniques and sophisticated computational algorithms, allow high resolution mapping of all the cells in a given tissue or organ.

Given these new capabilities, an international “Human Cell Atlas Consortium” published a white paper in 2017 outlining plans and strategies to build comprehensive reference maps of all human cells, organ by organ.  The intent of building such an atlas is to give a much better understanding of the biology and physiology of normal human tissues, as well as to give new insights into the nature of diseases affecting those tissues and to point the way to developing new therapies. 

One example of this new breed of cartography was published September 24 in the journal Nature, in a paper called simply “Cells of the Human Heart”.   This tour-de-force effort was led by scientists from Harvard Medical School, the Wellcome Sanger Institute, the Max Delbruck Center for Molecular Medicine in Berlin and Imperial College, London.  These teams and their collaborators analyzed about 500,000 cells from six different regions of the healthy adult human heart, using post-mortem organs from 14 donors.  They examined RNA and protein expression and mapped the distribution of different types of cells in each region of the heart.  In addition, they made comparisons of male and female hearts, and identified cells expressing genes known to be associated with different types of heart disease.  

One of the take-home messages from this study is that there is a lot of cellular complexity in the heart – with 11 major cell types (examples include atrial and ventricular cardiomyocytes, fibroblasts and smooth muscle cells), as well as multiple subpopulations within each of those types.  Also notable is the different distribution of cells between the atria (which are at the top of the heart and receive the blood) and ventricles (which are on the bottom of the heart and pump blood out): on average, close to half of the cells in the ventricles are cardiomyocytes, whereas only a third of the cells in the atria are cardiomyocytes.  Finally, there is a significantly higher percentage of cardiomyocytes in the ventricles of women (56%) than in the ventricles of men (47%).    The authors speculate that this latter difference might explain the higher volume of blood pumped per beat in women and lower rates of cardiovascular disease.  

The authors gave a few examples of how their data can be used for a better understanding of heart disease.  For example, they identified a specific subpopulation of cardiomyocytes that expresses genes associated with atrial fibrillation, suggesting that the defect may be associated with those cells.   Similarly, they found that a specific neuronal cell type expresses genes that are associated with a particular ventricular dysfunction associated with heart failure.    In addition, the authors identified which cells in the heart express the highest levels of the SARS-CoV-2 receptor, ACE2, including pericytes, fibroblasts and cardiomyocytes.  

Now that these data are accessible for exploration at www.heartcellatlas.org, I have no doubt that many scientific explorers will begin to navigate to a more complete understanding of both the healthy and diseased heart, and ultimately to new treatments for heart disease.