The Why, What and How of Stem Cells - a primer David Clapham CiP Conference Oct 2016

Why are we interested? Every cell in the body contains the same genetic material (DNA) Theoretically could become any cell type What differentiates a nerve cell from a skin cell? Which parts of the genetic code are expressed Different RNA and proteins Influenced by epigenetics, micro environment (O2,pH, pressure, architecture), growth factors ………… Exact mechanism still not always fully understood Stem cells much less specialised

Why do they exist? To make the organism

To maintain and repair the organism Typical adult human contains 50-75 trillion cells Cells are constantly dying (apoptosis) and being replaced In addition Trauma (e.g. cuts, bruises, muscle tears, broken bones) Environmental insults Pre cancerous events

What could Stem Cells be used for ? For fundamental research How do they form and differentiate How do organs develop What can go wrong and how can we stop it etc …………. For drug development Finding drug hits Toxicology testing (HEK cells) Making biopharmaceuticals (reagents) Some biopharms can only be made in mammalian cells Direct therapy – repairing/replacing damaged tissue Lab grown replacement tissues and organs

What has actually been done? Bone marrow stem cell transplants for blood cancers now common place (also useful in angina symptom control) Osteoarthritis trials very encouraging Osteoporosis/bone healing ‘very effective’ in early trials Stroke patients made a “remarkable recovery” in a trial that used donor stem cells injected into the brain Attempts to treat Cystic Fibrosis mixed success (too rapid cell turn over/too many issues?) –gene therapy may be more effective All successful direct therapy so far uses Adult Stem Cells (but HEK/embryonic cells used in research)

Cells with the ability to self replicate Cells with the ability to self replicate. They are either undifferentiated or poorly differentiated and can thus differentiate into different kinds of cell

Several Types Unipotent produce only one cell type Oligopotent can differentiate into only a few cell types Multipotent can differentiate into a number of closely related cell types e.g. bone marrow cells Pluripotent can differentiate into nearly all cells. Can be induced e.g. from skin cells Totipotent (a.k.a. omnipotent) stem cells can differentiate into all cell types. Such cells can construct a complete, viable organism.   In general the more potent the less abundant

How do they work?

Where can you find them? Embryos up to the first 2 or 3 cell divisions - Totipotent Amniotic fluid - potential source of pluripotent cells Chord blood - Multipotent Adult (mostly oligo or uni potent but can be multipotent with a few pluripotent) Almost any tissue which can be harvested. Bone marrow, Adipose tissue, blood, spleen, liver, skin etc

Can they be induced? In theory yes for all types In practice - IPS cells from skin cells (and renal epithelial cells)

What are the technical issues? Getting sufficient cells ? some rich sources - but numbers reduce with age damage increases with age collection not always straight forward Cells can be cultured to mitigate Sterility Identity Contamination HEK cells are now decades old Keeping them from differentiating Getting them to differentiate ‘properly’ Immunological (rejection) issues? not a problem if autologous Some success with donor cells (potential risk of DNA contamination) Dosing (right place, quantity and time) Funding Regulation

Possible Linked techniques Each of these has potential for good but also troubling ethical questions Sex cells derived from stem cells Heritable changes Cloning potential So called ‘3 parent’ cells (mitochondrial correction) Animal/human hybrids Genetic manipulation