By Heather Main

For many patients organ transplant is the only hope of survival or of living a close-to-normal life, but there aren’t enough organs for those who need a transplant. Donor incompatibility is another issue. Stem cell research is changing the way we view laboratory research, disease diagnosis and therapeutic possibilities. And when combined with ‘organoid’ and ‘decellularisation’ technologies, stem cell research is pioneering new ways to regenerate, repair or replace damaged organs and tissues that could revolutionize the field of organ transplantation.

Take a look at your hand. Poke it, clench your first, have a chew on your fingernails and marvel at its complexity. While your hand is really more of an appendage than an organ it is a pretty good example of just how complex it is to recreate a part of the body. The first thing you see is skin. Your hand is covered in skin, but underneath you have muscle, tendons, ligaments, bone, cartilage, blood vessels bringing blood cells, lymphatic vessels draining fluids, neurons sensing heat and touch or making the muscles contract, fingernails and all of this is held together with elastic fibre networks…imagine making a hand in the lab and getting all of those parts to function together (Picture 1)! You could apply this breakdown to any other part of the body or any organ to come to the same conclusion - it would be really complicated to make it in the lab!

Let’s go right back to the start, embryonic development. We all began our lives as 3 types of cells, or ‘germ layers’ which form the major components of the following organs:

  1. endoderm – digestive system, liver, lungs, thyroid etc.
  2. mesoderm –skeleton, cardiovascular system, fat, vascular, muscle etc.
  3. ectoderm – skin, eyes, nervous system etc.

To consider the ‘hand’ example again, all of the cells in your hand come from either mesoderm or ectoderm, but to produce distinct cell types may require very different signals and thus not be possible in a single in-vitro culture.   This is often illustrated as a tree with a trunk that forks in 3 directions and continues to branch to final leaves, each distinct leaf represents one functional cell type of the body. If you measure the distance to travel between 2 leaves you get an idea of how early in embryonic development they separated from each other.  For example the distance between cells of your heart and brain will be more than between your sweat gland and hair follicle. When we make cells from a particular organ in the lab we must decide which ‘branch’ to follow early on, and this restricts what we are capable of producing (Picture 2).

New techniques attempt to create more mixed cultures where one specific type of cell is not aimed for but rather whole branches of cell types are allowed to self-organise themselves into organ-like structures. While it may be more difficult to know exactly how your favourite cell type is behaving when it is mixed with other cells, some aspects of organ function may be easier to assess. The self-organising organ-like structures are less dependent on signals added by a scientist (thus less dependent on a scientist knowing what signals to add) and instead more dependent on the timing and signals produced by their neighbouring cells. A large part of creating organ-like structures in the lab is to have 3D scaffolds for the cells to live in, the elastic fibre networks that hold the cells of our organs together, enabling the system to function. Here we outline two pioneering methods – each with a different approach to recreating functional organs in the lab. The first utilises existing organ structures from donated organs to which cultured cells are added (re-cellularised organs) and the second, cells allowed to self-organise as mixed cell populations lay down their own scaffolds, somewhat disorganised compared to organs in the body (organoids).