Sunday, September 1, 2013

Stem cell therapy for achondroplasia?


Blogger offers some statistics about the visitors of this blog including the country from where the search was originated, read articles, which search engines were used to find the blog and the articles and, finally, the keywords used in those searches. It is easy to understand that achondroplasia, FGFR3, CNP, BMN-111, growth plate, “treating” and a lot of combinations of these expressions are the most common among them. Naturally, they are in the mind of people who think about the present and future of children with achondroplasia.

More recently, there has been an increasing incidence of keywords using expressions like “gene therapy” or “stem cell therapy” and “achondroplasia”, which I think is triggered by the constant news we have been frequently reading in newspapers or watching on TV. We have already briefly talked how there is no current published gene therapy for achondroplasia in this previous article. I think this article is the reason for the blog appearing in related searches.

In contrast, I am curious why searches using “stem cell” as keyword find this blog, since I never talked about this before. However, stem cells are indeed under the spotlight as a technique capable of replacing damaged tissue, rebuilding body organs and structures, rescuing a diseased brain and so on. Taking in account the interest in these developments recently, I thought it might be useful to talk about this topic. Nevertheless, in the same way we have been seeing in all those potential strategies for achondroplasia reviewed here, things related to stem cells (SC) are complex, too. So, it is important for the reader to understand that this article is only a panoramic view of the subject.

It is natural to ask

When we read about amazing scientific advances like SC therapies in the media we use to ask if they could be applied in situations that are familiar for us. So, it is likely that an individual with paraplegia (leg paralysis) will look for any information about the new SC therapies trying to rebuild damaged spine nerves; or someone with a very diseased heart will like to learn that there are institutions working on SC implants to make new heart muscle to rescue a severely infarcted heart.

Before you continue to read this text, try a simple query in Google: stem cell therapy paraplegia. You will retrieve thousands of sources about the topic, including scientific papers, newspaper articles, blogs, videos, etc. The same is valid for Parkinson disease or myocardial infarct or many other conditions deemed treatable with cell replacement. This article in Wikipedia will describe a lot of them to you. Well, one can quickly link: with so many possible applications can we use SC to rescue the bone growth disorder in achondroplasia?

What is a stem cell? And, could it be used in achondroplasia?

To understand if stem cells could be used in achondroplasia it will be good to review some concepts, starting by understanding about what these cells are.

Stem cells are undifferentiated cells with the property to become specialized cells, depending on the kind of stimulus they receive. Undifferentiated means that they are not using an uniform, so they can theoretically become policemen (leukocytes), truckers (blood red cells), constructors (osteoblasts), electricians (neurons), protectors (cells that cover surfaces such as the epithelial cells of the skin and mucosa), movers (myocites or muscle cells) or any other “worker” in the body (figure 1).

Figure 1. Stem cells.
From Mayo Clinic News Blog
But, how can this happen? How a cell with no identity can turn to be any other of the myriad of specialized cells working in the body? 

Each of the trillions of cells (1) living in the body have the same genetic code (DNA). However, each cell is specialized exactly because only a small part of the thousands of genes inside its DNA is active. It is the combination of the active genes inside a cell that makes it the kind of cell it is. Then, how does a cell know which genes should become active in a given context or environment? Scientists have discovered that the exposure to certain combinations of proteins or factors for a certain interval of time can trigger determined genes in stem cells leading them to transform into the kind of cells they want. They accomplished this by studying the growing of an organism from its first embryonic cell division (figure 2).

Figure 2. Example of embryonic development.
From Marten Postma Science webpage
The research has advanced a lot. The current knowledge classifies SC in at least three categories, although you will find more stratification, depending on the source. This article about stem cells in Wikipedia lists more sub-types of stem cells according to their flexibility in generating specialized cells, but the following are the key ones:
  • Totipotential stem cells (TSC);
  • Pluripotential stem cells (PSC);
  • Multipotential stem cells (MSC).
Although the roots of these names point to basically a similar capacity (toti, pluri, multi), each of them has distinct properties. For instance, TSC comprise only the cells resultant of the first embryonic divisions, the first 16 cells of a new embryo. These are the only cells capable to generate complete organisms, including some extra embryonic tissues such as the placenta.(2) PSCs are also obtained from the early embryo and can generate cells of all kinds but are not capable to create placenta. (2) Currently, it is also possible to create PSC from adult cells, using a complex technique of gene activation. (3) The resultant cells are called induced PSC (iPSC). The MSC are generally those stem cells collected from adult tissues that retain the capacity of becoming specialized cells from the tissue where they come from. These are the cells that allow the tissue or organ to substitute dying cells or heal from a wound.

Challenges to make stem cell therapies work

It looks like that you can pick some SC, put them into a culture plate, add some products into the culture like in a cookie receipt and then, wow!, here comes the new tissue, isn't it? Wish it was so simple. Scientists struggle a lot to find the correct formula to induce a MSC to become osteoblasts, myocites, neurons, epithelial cells or chondrocytes. Many experiences show that it is possible to generate these cells, but there are challenges to beat before they can be used in therapies including making them stay in the new shape; find their way to the target tissue (delivery); find the right spot in the target tissue or location to settle down; do what they are supposed to do when installed; do what researchers aimed them to do after all.

A stem cell-derived growth plate?

Now, imagine the challenges to accomplish all these tasks in the context of the growth plate. First, there is more than one kind of chondrocytes. Chondrocytes from the growth plate and from the articular cartilage are close relatives but do not behave exactly in the same way. What would be the right combination of factors to induce a SC to become a growth plate chondrocyte? This is a fair question, because most of the research in the field is directed to the articular cartilage, a fact that has also a good explanation. 

Osteoarthritis is becoming more and more common in an ageing population and, consequently, an increasing public health concern, so there has been a lot of research in techniques to repair a diseased joint with new tissue or to create a new organic joint to substitute the old one using SCs. Let’s imagine a plausible situation. You are 55 year old and used to be a very active individual. You keep working as the CEO of your company but there is something going wrong, you have a continuous pain in your knee that is preventing you to do walks or exercising. Your doctor will offer a meniscus replacement using your own SCs. The lab will grow a new meniscus and then the doctor will substitute the damaged meniscus for a brand new one in a couple of weeks. Today, this is still futurology, but it is a likely example of what could happen in a not so far future. You just have to browse the literature to find a number of initiatives towards articular cartilage reconstruction with SCs.

Now, let's take a look in this another example. Fine, someone has developed growth plate chondrocytes from an individual with achondroplasia bearing the right fibroblast growth factor receptor 3 (FGFR3) gene (remember, you will have to take the mutated gene out). Think about how to make these new cells “firing” the old ones and taking their places. You might have already read this previous article of the blog or learned from another source that the growth plate is not exactly an open freeway. On the contrary, the growth plate is built as a very well protected environment and usually large structures, and cells are large structures, would much probably not be able to enter there. 

Furthermore, there is not just one growth plate in the body. Each long bone has two growth fronts, in both extremities, and the other growing bones in a child also have their own growth plates. Therefore, simply injecting chondrocytes derived from SCs in the body would not be a certainty of success. They would have too many target spots to head to, a very complex task to accomplish. They could get lost and settle down in the wrong place.

All right then. So injections are not the solution. How can we be applying appropriate cultured chondrocytes to accomplish the goal of restoring the bone growth in achondroplasia? One could reproduce the scaffold represented by the cartilage matrix, and make chondrocytes grow inside. (4) This could possibly replicate the natural growth plate. 

But, then, how would he/she make this structure reach the bones? If one create growth plates in the lab, he/she will have to think in a way to substitute entire growth plates within the body, or at least, of those of the bones of interest. One would have to perform surgeries in all target bones, which sounds a bit hard after all technology applied. 

But this is just one challenge. Chondrocytes in the growth plate follow a very complex concert of chemical instructions, which are given through molecules coming from the vicinity (e.g.: CNP) or from far away (e.g.: GH, PTH). How would be the interaction between the newly implanted growth plate with this orchestrated program? And, to make it even a bit more complicated, growth plate chondrocytes grow in just one direction. A recent interesting study has demonstrated the consequences of a wrong growth plate re positioning. (5) How could we be sure that the implant was inserted in the right position?

Plenty of strategies at hand

Given the current knowledge in this field, today I think it is too much risk for a single mistake in a single gene. With the available technology it looks simpler to work in other fronts. There are several potential but feasible approaches to rescue the bone growth in achondroplasia, and most of them we have already reviewed in this blog. 

That is, one or more potential therapies for achondroplasia could already be available now. From preventing FGFs to trigger the receptor signal by blocking it with antibodies, aptamers, or small molecules, to “silencing” the mutated FGFR3 gene using RNA interference or morpholinos, or even counteracting the effects of the workaholic receptor with other compounds such as CNP (BMN-111 is one example), there are several strategies just waiting to be explored. However, they are still in the labs because there is not enough investment to develop them. 

To review some of the above mentioned strategies just visit the blog's English page, by clicking the respective button on the top of this page. 


1. Bianconi E et al. An estimation of the number of cells in the human body. Ann Hum Biol 2013 Jul 5. [Epub ahead of print]. (doi:10.3109/03014460.2013.807878).

2. Laboratório Nacional de Células-tronco Embrionárias - Rio de Janeiro. Células-tronco, o que são? Universidade Federal do Rio de Janeiro. Visited in 25 August 2013. (Portuguese) (What are stem cells? Federal University of Rio de Janeiro; free translation).

3. Takahashi K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131(5):861-72. (Free access).

4. Elder S et alAttachment, proliferation, and chondroinduction of mesenchymal stem cells on porous chitosan-calcium phosphate scaffolds. Open Orthop J 2013;7:275-81. (doi: 10.2174/1874325001307010275). (Free access).

5. Hadju et al. Growth potential of different zones of the growth plate — an experimental study in rabbits. J Orthop Res 2012; 30:162-8.


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