Here’s how your brain stem cells can turn back time.
Stem cells are magical ✨ Ok, maybe not 𝙢𝙖𝙜𝙞𝙘𝙖𝙡 but the field has made some huge advancements in the last few decades. By adding just four factors to normal cells, we can turn back time.
And by that I mean we can make regular adult stem cells into cells that can turn into any cell type in the entire body. That’s great and all but we’ve only been able to do this in vitro, in a lab. Now, what if I told you that a process like this already exists in the body?
🤯 ← That’s you when you heard that.
But let’s start at the beginning, back when we used to think that differentiation of stem cells was a one-way street, and talk about what stem cells even are. (Pssst, if you already know all about stem cells, you can click here or go to the section titled “Part II: It Was Inside Of Us All Along.”)
Part I: The Magic of Stem Cells
What Are Stem Cells?
Stem cells are kind of like the baby cells of the body. This doesn’t necessarily refer to how old they actually are but to how potent they are. When talking about stem cells, potency is their ability to turn into other cell types!
Think of it like this. First off, we have totipotent stem cells, the infants. They barely have an understanding of the world around them and so they’re clueless about what they want to do with their life. They can turn into any of the cell types in the entire body; that’s over 200 types!
Next up is pluripotent stem cells and they’re a little older, maybe 5 or so. They may have a super vague idea of what they want career-wise but not really. And so they can turn into any cell type except extraembryonic cells, those outside the embryo.
The last one we’ll need to cover for today is multipotent stem cells, and they’re quite a bit older and in high school. They have a pretty good idea of what field they want to go into. Maybe medicine 🩺 or maybe art 🎨 So, they can only turn into cells of a specific group, like kidney cells or skin cells. Keep in mind that there are subsets of cells within those organs.
When stem cells go from one of these states, totipotent, pluripotent, and multipotent, to another, they’re differentiating and losing potency.
To sum it all up, let’s create a checklist. If you wanted to be a stem cell you’d have to check off these two things (and of course… be a cell)
❐ Be able to self-renew. That means be able to create copies of yourself.
❐ Be able to differentiate into other cell types.
The 3 Germ Layers
Even though the word germ is in it, it’s really not as gross as you might think!
When stem cells go from pluripotent → multipotent, they become part of one of the three germ layers: the ectoderm, mesoderm, or endoderm.
How do these layers form though? To understand, we need to take a quick look at some developmental biology 🍼
At around 15 days after the fertilization of the egg (aka when the sperm enters the egg), we reach a stage called gastrulation. At this point, there’s something called the bilaminar disk at the top of the embryo.
This disk goes through a process and a third layer is created; now we’ve got a trilaminar disk! Feel free to watch this video for some visualization of the process.
Now can you guess what the 3 layers of the trilaminar disk are? Yep, the ectoderm, mesoderm, and endoderm.
Now onto why these layers even matter. The ectoderm is the outermost layer. An ectoderm cell can become a skin cell of the epidermis, a neuron, a pigment cell, and more.
The mesoderm is the middle layer. Think “m” for middle. It can differentiate into muscle cells, tubule cells of the kidney, red blood cells and many others.
Finally we come to the innermost layer–the endoderm. It can turn into the cells for the lungs, thyroid, pancreas, and quite a few of the organs in general.
The Waddington Landscape
Let’s get back to our main topic of stem cells! As they differentiate, they get closer to their final identity but also farther away from all of the other identities.
But we can take another step towards simplifying this using the epigenetic landscape that Conrad Hal Waddington came up with.
Epigenetics, like genetics (the study of our cell recipe, DNA), tries to tackle what determines how our cells operate. However, unlike genetics, it’s not written in our DNA. Epigenetics is a layer above genetics and it can change over time. It’s how DNA interacts with molecules within our body!
While it’s not changing our DNA, epigenetics certainly does affect our health and our body as a whole. If our DNA is the writing of the recipe to our cells, epigenetics is like the font. It doesn’t change the content but it is still a considerable change. (You can learn more by watching this TED-Ed video.)
Now with that out of the way, let’s get back to stem cells and Waddington. He imagined stem cell differentiation as an epigenetic process where the totipotent stem cells at the top would roll down valleys and eventually reach their end state as a fully differentiated cell.
A fancy way of saying this is that differentiation is unidirectional. There’s no way to go turn these stem cells back into their undifferentiated selves. Pretty cool right?
Sure, the science is awesome but if we could turn these cells back into pluripotent ones, we could do so many awesome things like tissue regeneration, stem cell replacement (if your stem cell supply becomes depleted), and treat or possibly cure diseases like spinal cord injuries, type 1 diabetes, Parkinson’s disease and more!
Induced Pluripotent Stem Cells
But wait. I have a confession. I lied to you. The Waddington landscape isn’t unidirectional! In fact, we’ve known the idea of unidirectionality to be false ever since 2006.
That’s when the famous paper by Kazutoshi Takahashi and Shinya Yamanaka came out, telling us about how using just four factors, Oct3/4, Sox2, c-Myc, and Klf4, we could turn back time for differentiated mouse cells! In other words, we can turn these differentiated cells into pluripotent stem cells.
Just a year later, they were able to do the same for adult human fibroblasts (Fibroblasts are important for connective tissue and more importantly, they are already differentiated.)
They decided to call these pluripotent stem cells, Induced Pluripotent Stem Cells or iPSCs for short.
Now, unfortunately, this could only be done in vitro, in a lab. We didn’t know if this happened naturally within the body. Until…
Part II: It Was Inside Of Us All Along
February 2021–when this paper by Antoine Zalc and Rahul Sinha came out. This is when we finally found out about how cranial neural crest cells (CNCCs for short) are able to be part of both the ectoderm and the mesoderm germ layers!
These CNCCs are bipotent which means they can turn into both mesenchyme, coming from the mesoderm, and neural and glial progenitors, coming from the ectoderm.
Just let that sink in. For decades, stem cell biologists have been taught that going down the Waddington landscape is a one-way trip. Then the entire idea was flipped on its head when Yamanaka discovered iPSCs. And now we know that there are cells that can reprogram themselves naturally to become part of two germ layers. And they’ve been inside of us all along!
Somitogenesis
Quick lesson before we go any further. Let’s talk about somitogenesis!
This is the process by which somites are formed. And somites are basically just balls of mesoderm.
These somites eventually give rise to skeletal muscle, cartilage, tendons, and more!
So How Does This Work?
Back to the amazing CNCCs! To help us better understand what these amazing cells are doing, we can use the Waddington diagram again.
What these cells are doing is that they “climb back up” the hill to CNCCs that have Oct4 in them and from there they either become part of the mesoderm or the ectoderm.
Remember from before that Oct4 was one of the factors used to create iPSCs. Isn’t it crazy how Yamanaka came up with a reprogramming process while the body has been doing something similar completely independently?!
Now let’s dig a little deeper into the science behind it. Using single-cell RNA-sequencing analysis (a fancy method you don’t have to worry about), the researchers were able to identify the diversity between the cells during different somite stages.
And they found two major cell clusters; one was neuroepithelial precursors (ectoderm) and the other was migratory mesenchymal CNCCs (mesoderm).
Starting off at the 4-somite stage, most cells went to the neuroepithelial cluster.
Then at the 6-somite stage, there was an abrupt switch and the cells in the embryo became delaminated and started expressing genes specific to the neural crest!
All you have to know about delamination is that it’s an essential process for the transition from the epithelial to the mesenchymal state. CNCCs are originally known as epithelial cells but can then transition into mesenchymal cells.
By the 8-somite stage, most cells were in the migratory mesenchymal CNCC clusters and underwent their very first commitment decisions where they separated into mesenchyme or neural/glial progenitors.
An even more interesting finding was that neuroepithelial precursors could be broken down further into two more categories, each of which had a high level of the factors Otx2 or Gbx2 but not both.
Those with high levels of Otx2 could be found in the anterior while those with high levels of Gbx2 in the posterior. (Anterior just means near the front of something and posterior means towards the back.) Look at the diagram below that shows this!
But these positional identities were erased during delamination because there was only one group of delaminating CNCC cluster.
Why Should I Care?
Great question! While basic science papers like the one I based this article on often go ignored by the general public, it’s how we make progress in all fields of science.
We first need to understand the mechanisms behind these processes before we can apply them to real-world medicine or treatments.
This paper specifically is mind-blowing because it shows that a process we discovered in the lab is happening naturally inside the body! Where else inside the body could this be happening? How could we induce this naturally to treat diseases? The applications are endless!
TL;DR
- Stem cells are able to self-renew and differentiate into different cell types
- There are 3 germ layers–the ectoderm, mesoderm, and endoderm– and each of them contributes to certain cells within the body
- We use to think that the Waddington landscape was unidirectional → there’s no way to turn differentiated cells pluripotent again
- But that was proven wrong with iPSCs and now cranial neural crest cells!
Since you’ve made it to the end you deserve a few prizes!
🎁 If you’re interested in developmental biology, this video is an awesome start.
🎁 This one is also pretty cool and about early embryogenesis.
🎁 Final recommendation is an amazing podcast that you need to check out right now. It’s called The Stem Cell Podcast and it’s all about culturing stem cell knowledge. (They also have some pretty amazing guests!)
Hey there 👋 Parmin here; I’m a 15 y/o student studying stem cells at The Knowledge Society 🧪 Everyday, I aspire to uncover the secrets of biology and learn something new! Make sure to follow me on Medium to hear about every new article I post, connect with me on LinkedIn, or contact me at parminsedigh@gmail.com! Also subscribe to my monthly newsletter to learn about every cool, new thing I’m working on ✍️
References
Feel free to check out all of my references right here.
