8 - Stem cells 

  • Unspecialised cells 

  • Capable of self renewal - divide and multiply in their unspecialised state to generate more stem cells (identical daughter cells) 

  • Can differentiate to give rise to specialised cells (adopt a different phenotype)



  • Stem cells do not differentiate directly into specialised cells 

  • They give rise to progenitor cells that have limited capacity to self-renew before differentiating 



Nomenclature 

Potency 

  • Totipotent - capable of forming every cell in the embryo and placenta (not stem cells because they do not self renew) 

  • Pluripotent - can for every cell in embryo not placenta (embryonic stem cell) 

  • Multipotent - form a range of different stem cells (hematopoietic stem cells)

  • Unipotent - generate one type of specialised cell (spermatogonia)




Pluripotent stem cells 

  • Embryonic stem cells - present in the pre0-implantation embryo 

→ blastocyst 

- Induced pluripotent stem cells 



Somatic or ‘adult’ stem cells 

  • Present in a variety of adult and foetal tissues 

  • More restricted potential and not immortal

  • Embryo - week 5 to 10 of pregnancy - important organs and systems begin to form - cells divide to allow this 

  • Foetus - week 10 until birth - goes through rapid development - organs and systems further developed - begins to look more like a human 








Pluripotent 

  • Immortal 

  • Give rise to any cell type in an embryo 





Embryonic stem cells 


The blastocyst 



Isolation of embryonic stem cells (ES)

  • Use of leftover IVF stem cells 


  • Nucleus takes up greater volume of the cells 

  • Prominent nucleoli 








  • By day 7 - embryonic stem cells are no longer present 

  • They have already rapidly differentiated into epiblasts and hypoblast 








Applications of stem cells 


  1. Scientific discovery (pluripotent stem cells) 

  • Can inform how particular cell types and tissue form during embryo development 

  • Can be used to understand disease mechanisms 


Organoids - an artificially grown mass of cells or tissue that resembles an organ 


Synthetic embryo models 

  • Developed in the lab  

  • Usually for the purposes of research 

  • Able to investigate molecular mechanisms that regulate human embryogenesis 

  • Somewhat overcomes the limitations of using natural human embryos 

  • Has been started on humans - ethical concerns 

  • Building blocks are embryonic stem cells 





  1. Drug development 

  • Can enable rapid screening of large numbers of drugs/chemicals 

  • Reduced number of animals needed for drug testing 

  • Rule out at the start of the development process any drugs that are dangerous or not effective

  • Useful for generating cell types that cannot be easily obtained from primary source (eg. neurons from CNS) 

  • Personalised medicines 



  1. Gene therapy 

  • Blistering of the skin - can develop septicemia




  • Approach has be successful:


Novel stem cell / gene therapy for treating EB 


Patient: young boy with mutation in a gene encoding laminin beta3 

Treatment: skin biopsy taken. Cells infected with a retrovirus bearing healthy copy of LAMB3 - grew into sheets 

Outcome: after a month, most of the new skin had begin to regenerate 



MLD 

£2 million 

Hematopoietic stem cells used




  1. Production of specific cell types for therapeutic transplantation 

  • Adult stem cell based therapies already used in humans (eg. bone marrow transplant) 

  • Isolation of first human embryonic stem cell lines in 1998 - potential for treating a range of conditions; Parkinson, diabetes, age related macular degeneration (ARMD) 


Bone marrow transplant and leukaemia 

  • Hematopoietic stem cells is what is used 


  • Hematopoietic stem cells can also treat: sickle cell, 












Technical barriers and possible solutions 

  1. Risk of tumour formation 



  1. Difficulties in stem cell behaviour regulation

  • Hard to direct an entire population of pluripotent stem cells to become one particular cell types 









  1. Tracking cells following administration 

  • Hard to monitor where they go after they have been administered to the patient 

  • If the go to non-target organs - this could have adverse effects 

  • If only a few go to target organ - may not be beneficial effects 

  • Imaging technologies required to track the cells 


Biodistribution data 


To assess safety - need to know which organs and tissues the cells have populated in order to assess potential adverse host reactions 


  • Bioluminescence imaging - stem cells expressing firefly luciferase

  • Shows that the cells can form tumours in the long term 



  1. Immune rejection 

Solutions: 

  • Immunosuppressants (adverse side effects) 

  • Generate pluripotent stem cells that are genetically identical; to the patient's cells 

  • - Achieved by reprogramming patients somatic cells to adopt a pluripotent stem cell fate (induced pluripotent stem cells)

  • Use genetically matched pluripotent stem cells