A Few Recent Advances in Tissue Engineering and Regenerative Medicine

The tissue engineering and regenerative medicine communities are too large and energetic to do more than sample their output, or note the most interesting advances that stand out from the pack. The publicity materials I'll point out here are a recent selection of items that caught my eye as they went past. Dozens more, each of which would have merited worldwide attention ten or fifteen years ago, drift by with little comment every year. The state of the art is progressing rapidly towards both the ability to build complex tissues from a cell sample, such as patient-matched organs for transplantation, and the ability to control regeneration and growth inside the body. Ultimately we may not need transplantation if native organs can be persuaded to repair themselves ... but this will likely also require significant progress towards repairing the cell and tissue damage of aging, the forms of molecular breakage that degrade regenerative capacity.

Even though the research community has progressed a long way past the capabilities of even a decade ago, there remains a longer road ahead. Transplants of cell populations are still very challenging; only a small fraction of those cells survive to take up residence and contribute over the long term. The best technology demonstrations manage 10% survival or thereabouts. Standard approaches to finding the best methodology for each cell type and situation have yet to arise. There is a lot of trial and error. Yet replacement of cell populations, reliably, and with high quality, youthful, undamaged cells, is needed to treat many of the consequences of aging. Consider the loss of dopamine-generating neurons in Parkinson's disease, for example, or the wearing down of the stem cell population responsible for generating the immune system, or the structural remodeling and weakening of the heart in response to hypertension. Removing the damage that caused those issues will not automatically restore all of the losses.

Researchers report first lung stem cell transplantation clinical trial

For the first time, researchers have regenerated patients' damaged lungs using autologous lung stem cell transplantation in a pilot clinical trial. In 2015, the researchers identified p63+/Krt5+ adult stem cells in a mouse lung, which had potential to regenerate pulmonary structures including bronchioles and alveoli. Now they are focusing on lung stem cells in humans rather than mice. The researchers found that a population of basal cells labeled with an SOX9+ marker had the potential to serve as lung stem cells in humans. They used lung bronchoscopy to brush off and amplify these lung stem cells from tiny samples.

In order to test the capacity of lung stem cells to regenerate lung tissue in vivo, the team transplanted the human lung stem cells into damaged lungs of immunodeficient mice. Histological analysis showed that stem cell transplantation successfully regenerated human bronchial and alveolar structures in the lungs of mice. Also, the fibrotic area in the injured lungs of the mice was replaced by new human alveoli after receiving stem cell transplantation. Arterial blood gas analysis showed that the lung function of the mice was significantly recovered.

The team launched the first clinical trial based on autologous lung stem cell transplantation for the treatment of bronchiectasis. The first two patients were recruited in March 2016. Their own lung stem cells were delivered into the patients' lung through bronchoscopy. One year after transplantation, two patients described relief of multiple respiratory symptoms such as coughing and dyspnea. CT imaging showed regional recovery of the dilated structure. Patient lung function began to recover three months after transplantation, which maintained for one year.

Scientists create functioning kidney tissue

Kidney glomeruli - constituent microscopic parts of the organ - were generated from human embryonic stem cells grown in plastic laboratory culture dishes containing a nutrient broth known as culture medium, containing molecules to promote kidney development. They were combined with a gel like substance, which acted as natural connective tissue - and then injected as a tiny clump under the skin of mice. After three months, an examination of the tissue revealed that nephrons: the microscopic structural and functional units of the kidney - had formed.

Tiny human blood vessels - known as capillaries - had developed inside the mice which nourished the new kidney structures. However, the mini-kidneys lack a large artery, and without that the organ's function will only be a fraction of normal. So, the researchers are working with surgeons to put in an artery that will bring more blood the new kidney. "We have proved beyond any doubt these structures function as kidney cells by filtering blood and producing urine - though we can't yet say what percentage of function exists. What is particularly exciting is that the structures are made of human cells which developed an excellent capillary blood supply, becoming linked to the vasculature of the mouse. Though this structure was formed from several hundred glomeruli, and humans have about a million in their kidneys - this is clearly a major advance. It constitutes a proof of principle - but much work is yet to be done."

New tissue-engineered blood vessel replacements closer to human trials

Researchers have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doesn't contain any living cells at implantation. The vessel, that could be used as an "off the shelf" graft for kidney dialysis patients, performed well in a recent study with nonhuman primates. It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted.

The researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation.

To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection.


I saw this article recently on improving stem cell engraftment into muscle fibres:


"Stem cells hold promise for diseases such as muscular dystrophy because of their ability to differentiate or produce new cells that can form into specialized tissues in the human body. In theory, stem cells could replace damaged tissues with new tissue, unaffected by disease.

However, scientists have had difficulty developing successful treatments, especially for muscle, because once the stem cells are isolated in a lab dish, they stop simply being stem cells and begin to differentiate. In this case, the muscle stem cells stop dividing and become muscle fibers, which do not transplant well.

"Stem cells are like flour-they can be baked into any number of things like pies, cookies, or bread-but once that happens, there is no going back to flour," said Fabio Rossi, Ph.D., professor of medical genetics at UBC's biomedical research center and school of biomedical engineering, and senior author of the paper. "The problem was that all our stem cells were turning into 'bread' and we really needed them to stay as 'flour' so they could continue to replicate, creating enough cells so that we can transplant and regenerate the tissue effectively."

"This discovery unveils a new method to boost the therapeutic potential of muscle stem cells, allowing these cells, when transplanted into damaged tissue, to facilitate tissue regeneration and improve muscle function,"....

...Setd7, the UBC scientists learned, plays a role in controlling stem cell growth and their maturation into muscle fibers. Using their Setd7 inhibitor, the scientists were able to prevent immature, transplantable myogenic stem cells (MuSCs) from differentiating so that these cells could continue to divide. Then the scientists implanted the stem cells into the hind leg of mice affected by a mouse model of muscular dystrophy."

Posted by: Jim at February 9th, 2018 7:08 PM

Nothing of this will become useful if we cant develop cryoprotectants. cryoprize currently at $2495,98 of $33.000 goal.


Posted by: Norse at February 10th, 2018 5:29 AM

@Norse - how is the cryo prize different to that organ preservation alliance prize that the Methuselah foundation is involved in?

Posted by: Jim at February 10th, 2018 7:11 PM

Great prospects for derivatives of iPSC
A new forum from Hiromitsu Nakauchi and colleagues on "iPSC-Derived Organs In Vivo: Challenges and Promise"
Transplanting iPSCs into the embryos of another species can generate functional organs for basic research and translational applications. We discuss forward-looking approaches and address key remaining challenges of generating iPSC-derived human organs in vivo.

A functional human liver model can be constructed in vitro from the liver non-parenchymal cells (NPCs) such as liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) derived from hiPSCs. http://www.cell.com/stem-cell-reports/abstract/S2213-6711(17)30273-4

Jason Spence and colleagues show that iPSC-derived bud tip progenitors can engraft into an injured mouse airway, contribute to re-epithelialization, and differentiate into multiple lung epithelial lineages. http://www.cell.com/stem-cell-reports/abstract/S2213-6711(17)30519-2

Posted by: Dmitry Dzhagarov at February 11th, 2018 12:25 AM

If you look at the details on Organ Preservation Alliance (OPA) page you will see that they dont have any prize. They collect money to research directly. Both approaches are critical. If you read the papers, today 60-70% of donated lungs and hearts are wasted because they dont have technology to cryopreserve them well enough and it is estimated that if they could preserve them well the current waiting list would be away/dissapear in 2-3 years.

Methuselah Foundation (MF) who launched New Organ (NO) are not involved in OPA but NO helped launch OPA. But that have the same interests. NO have a prize.

Posted by: Norse at February 11th, 2018 5:38 AM

Its worth mentioning if you read the papers available at OPA and Solving Organ Shortage (SOS), sites if we all live long enough through advances in gerontology 1/3 of population will need an new organ. This is critical for all of us not only they who are waiting for organs under current criteria. Criteria will be expanded when more organs get available. It is estimated that current need for organs are 10X larger than today's waiting lists show.

Posted by: Norse at February 11th, 2018 5:41 AM

@Dmitry Szhagarow: Thanks for the URL's. I hadn't seen that.

Posted by: Norse at February 11th, 2018 5:44 AM

And of course, which I dont need to write because everyone who have been here at forum for som time knows and understand if you are thinking about signing up for cryonics or support the practice you should support both Cryoprize and OPA with your money so cryoprotectants are improved. This dont need explanation but maybe for the new readers here.

Posted by: Norse at February 11th, 2018 6:06 AM

@Norse: There is also the possibility (for the whealtier) to invest in Arigos: https://www.arigosbiomedical.com/ I wonder whether the Methuselah Fund have plans to invest on it.

Posted by: Antonio at February 11th, 2018 6:21 AM

@Antonio: Thanks. I didn't knew it was open for investment. Hope they do an IPO in future so it can be possible to invest for small savers like myself. And hope MF/NO/OPA invests.

Posted by: Norse at February 11th, 2018 6:33 AM

Well... I'm not sure whether they did an IPO, but recently Aubrey said that they are in need of funding, so I assumed people can invest in it...

Posted by: Antonio at February 11th, 2018 10:40 AM

If I any person today that thinks about saving money for cryonics its a better strategy to donate to cryoprize and Organ Preservation Alliance (OPA) because when we get better cryoprotectants more people will sign up for cryonics, it will be cheaper, vice versa.

Posted by: Norse at February 11th, 2018 11:33 AM
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