The Future of Organ Transplantation is in the Plant Kingdom
In the ancient world, there were alchemists who thought they could turn lead into gold. It’s known as “a quest for material perfection, in which humans and nature collaborate.” Maybe we can’t turn lead into gold, but turning something of lower-value materials in nature into something worth greater? I think the alchemists were onto something.
Recently, plants have been showing great promise in biomedical research as an organ transplant biomaterial. This means we could potentially turn an apple, which costs little to nothing, into a vital organ. This, however, isn’t alchemy. This is tissue engineering.
The organ transplant wait-list is only getting longer each day, with hundreds of thousands of people waiting for an organ that could potentially save their life. Countless researchers, all standing at the frontlines to battle the palisades of innovation, but all discoveries come with their own baggage and challenges. Current solutions are animal-derived, or from cadavers or proprietary products, all of which are expensive and controversial. Infection, costliness, and ethical issues plague this field, hindering an effective solution to this age-old problem. But there seems to be a new promising contender that may be a light at the end of the tunnel: Plants. So what do you say, can we put the plant in organ transplant?
Why Plants?
The plant kingdom has an appealing variety of scaffold biomaterials that have yet to be investigated to their fullest potential. But why the plant kingdom? Plant tissues are inexpensive, widely available, lack ethical issues, surprisingly structurally similar to human tissue, and have biocompatible molecules making them leading contenders for clinical applications and research. Plants present a promising environment because of their unique porous structure and innate vasculature, which is really difficult to recreate synthetically. Even though there are 3D bioprinting approaches, those aren’t as accessible and very expensive. Recent research demonstrates tremendous similarities to the molecular level between the structure and function of the plant cell wall and the human extracellular matrix. (more on this later!)
I really hope there’s a future where people walked around saying “Hey, that guy has an apple for an ear, or a celery for a spinal cord, or a strawberry for a heart.” Or if you accidentally cut your thumb while cutting meats in the kitchen, and you just take a piece of carrot to biorepair yourself. This might not be too far from reality, research in this field has been incredibly promising! But how does this whole process work?
FUNdamentals of Tissue Engineering and Scaffolding
Tissue engineering is revolutionary and can save millions of lives through stem-cell therapy and tissue regeneration. We can create organs from scratch. To do this, we need scaffolds, which mimic the human extracellular matrix.
Wait, what’s a scaffold? They’re artificial extracellular matrices (ECM).
First things first, what is the extracellular matrix? Every living thing on earth is made of this common thing: cells. The extracellular matrix provides a support structure for the cells to adhere on to, communicate with each other, proliferate, migrate and differentiate. It’s a mesh framework composed of fibers, collagens, proteoglycans, elastin, proteins and cell-binding glycoprotein. It makes mitosis and meiosis possible, critical processes for cell production. The extracellular matrix is super similar to a social media platform in that sense, a support structure that many rely on for their social lives, playing a role in how people communicate with each other, and allowing for group chats, similar to how the extracellular matrix segregates tissues.
An extracellular matrix is made of 4 main components:
- Collagen fibers: gives tissues strength and structure.
- Proteoglycans: class of glycoproteins that have a lot of carbohydrates and sugar molecules, linked together to form chains. They interact with growth factors, and help in cell signaling and biological processes, like angiogenesis (blood-vessel formation).
- Integrins: anchor the cell to the extracellular matrix. They detect chemical cues from the extracellular matrix and trigger signalling pathways in response.
Eg. blood clotting. When cells are damaged in the blood vessel, they show a protein receptor called tissue factor. Tissue factor binds to a molecule in the ECM, triggering responses to reduce blood loss.
4. Fibronectin: A biological glue that binds integrins to collagen and proteoglycans, reaching the receptors of the cell.
Dang, that’s a ton of info. Key points: ECMs are a structure of many collagens, proteins, and glycoproteins that help the cells grow by providing support. They also have complex signaling pathways so the cells can communicate with one another. We have ECMs to generate organs and tissues. The goal for plant scaffolds is to grow organs that can eventually be implanted into the human body, without taking organs from animals, cadavers, or people. We need scaffolds to be stand-in ECMs for in-vitro cell growth.
Scaffolds are any porous, mesh-like structure used to encourage cell growth. The pores are necessary for the cells to infiltrate it, allowing for nutrient diffusion (transportation) and for the cell to occupy the whole scaffold. The biggest challenge in tissue engineering is finding a suitable biomaterial for scaffolding.
There are four main criteria for ideal scaffolds:
- Biocompatibility: allows cells to adhere, multiply, function
- Biodegradability: after implanted in the body, produces non toxic by-products, and allows cells to produce an extracellular matrix
- Mechanical properties: strong enough not to break while handled by surgeon, consistent with the implant site
- Scaffold architecture: porosity for cell infiltration, nutrient diffusion
Many biomaterials today fail in achieving the biological, structural and vascular properties required for scaffolding.
Organogenesis in the Body
During gastrulation ( an early phase in embryonic development), cells migrate to organize themselves to form 3 layers of cells: the endoderm (gives rise to the nervous system and epidermis), ectoderm (gives rise to the gut and internal organs) and mesoderm (gives rise to muscle cells and connective tissue). An embryonic cell then expresses a certain gene, and turns into a specific tissue cell type (eg. a skin cell) to soon become an organ. Organogenesis is the process in biology where embryonic stem cells transform and form organs.
Embryonic cells in the endoderm are responsible for internal organs (pancreas, liver, etc), some of the cells will express the genes to become pancreas, while some become liver cells. The process of cell differentiation in the germ layers produces the tissues and organs in our bodies.
Organogenesis in the Lab
- A cell sample is taken from the patient (must be stem cells that have regenerative potential and are specialized to the tissue the patient needs)
For example, for bone tissue, you would need a sample of MSCs (mesenchymal stem cells).
2. The cells are then tricked into thinking they’re in the human body by supplying them with medium, typically DMEM (Dulbecco’s Modified Eagle Medium), and FBS (Fetal Bovine Serum) to provide sugars, salts, proteins and nutrients, and the right environment in an incubator (37°C and 5% CO2 levels). By tricking the cells, they will naturally grow and proliferate (multiply like usual and grow in numbers).
3. The cells then differentiate or turn into their tissue-specific cell type, by feeding it added growth factors to encourage the cells to change. This is because we tricked the cells into thinking they were in the human body. Mesenchymal stem cells would turn into bone cells, given the right added media to induce it.
4. Scaffold is implanted into the body. Over time, the plant scaffold will disintegrate, and the cells will have formed an extracellular matrix in its place, restoring a vital organ.
From Plant to Organ Process
To use plant scaffolds, first we must decellularize plant tissues. Then we implant stem cells into the scaffolds so they can multiply and grow like normal. The cells then differentiate into their tissue-specific cell type (liver, pancreas, you name it!). Now, the scaffold is ready to be implanted into the body, where it degrades over time, leaving an ECM in its place.
Decellularization is essentially removing all the plant cells and DNA to leave behind an empty cellulose scaffold, which is just the plant cell wall. To decellularize a plant tissue, baking soda and bleach is used to dissolve the cellular membranes, which will then be extracted through cleansing the tissue. This process leaves behind the cell wall which is the plant structure, just without the DNA . It keeps the fragile structure of the plants like their pores and vascular bundles intact, which is key to leveraging the entire 3D environment of a plant tissue. Now, there’s no reason we have to implant plant cells back into the scaffold. So what would happen if we implanted human cells?
First, we need to prepare the human cells. In order to turn the original cells from stem cells into tissue-specific cells, we need a medium to provide cells with food and nutrients. Currently, we use DMEM which contains lots of glucose (sugars), salts, amino acids, proteins and vitamins, necessary for the cells to grow and survive. DMEM is used along with fetal bovine serum (FBS) (baby cow blood). FBS has a high content of embryonic growth factors, like hormones, macromolecular and carrier proteins. These mediums maximize proliferation which is crucial to organ formation. Additional growth factors are added for the cell to differentiate into their tissue-specific cell type.
The scaffolds are soaked in this medium to encourage the cells to adhere to the walls of the pores and to promote nutrient absorption. Then the cells are implanted into the scaffolds, and allowed to proliferate and differentiate like they would in the body.
To provide the optimal environment for cell growth, we need an incubator. An incubator is essentially a warm, humid box at the heart of any biology lab. It provides a controlled, contaminant-free environment for reliable biomedical research with cell cultures. Cells need specific conditions in temperature and CO2, which is 37°C and 5% CO2, because this is what they’re used to in the body. Giving cells every condition they’re used to, effectively tricks them into thinking they’re still in the body, and perform natural cellular functions, like proliferation and differentiation.
Once the cells have successfully differentiated into their tissue-specific cell type, the scaffold can then be implanted into the body. Recent research in mouse models shows that the body actually sends the scaffold nutrients and a blood supply to help it grow and stay alive. Eventually the scaffold will disintegrate (which is why it’s so critical for it to be biodegradable!), while the cells are hard at work building a natural extracellular matrix in its place, restoring a vital organ.
What’s stopping it from coming to market?
Plant-derived scaffolds have only just come into play. Only in 2017 did we have 2D plant scaffolds derived from basal and spinach leaves, and through their veins, we recreated smaller blood vessel tissue. It was only recently that we started experimenting with 3D plant tissues, like apple for adipose tissue, carrot for bone tissue, celery for tendon tissue, asparagus for spinal cord tissue. Plant scaffolds have only been uniform in nature so far. But in the future, we’ll likely have more research on more complex, vital organs like the heart, lung or liver.
TL;DR:
- Tissue engineering is a revolutionary technology that mimics organogenesis, a process to form organs during the embryonic development stage, to create tissues and organs.
- The ECM (extracellular matrix) provides structural support for the cells (made of glycoproteins, collagens, enzymes) to promote cell growth and development.
- Scaffolds are a porous, mesh structure, and are a stand-in for the ECM for in-vitro cell cultures.
- Plants are a front-runner for scaffold materials because they’re low-cost, accessible, have biocompatible molecules, and structurally similar.
- From plant to organ process:
1. Stem cells are taken from the patient
2. We decellularize a plant tissue, to create a plant scaffold
3. We recreate the same conditions in the body for the cells, like temperature, nutrients given, and CO2 level, to trick the cells into growing.
4. The stem cells are implanted onto the scaffold to multiply and differentiate into their tissue-specific cell type
5. The scaffold is implanted into the human body and disintegrates, leaving behind a natural ECM in its place, to restore a vital organ.
Labs Working on this:
Many centuries ago, alchemy was a primitive practice, and not exactly science. At this moment, we can only dream of it. Even though we can’t turn lead into gold, the pursuit of transforming materials is still bursting with life. Today, we can turn this into reality. We can collaborate with nature to find innovative solutions to the world’s biggest problems, and use plants to tackle the ever-growing organ transplant waiting list.
If you made it this far, I have to say, you have amazing taste in the articles you read, especially in the authors you read them by. Have an awesome day, ok? Yeah, you. You reading this. You deserve the world. ~victoria
