Stem cells and regenerative medicine Flashcards
What are stem cells?
Can differentiate into many different cell types Capable of self-renewal via cell division Provide new cells as an organism grows and can replace cells that are damaged or lost Several different types of stem cells: embryonic, adult and induced pluripotent stem cells Targeted by researchers for their therapeutic potential
What do each of the 3 germ layers give rise to, as examples?
Ectoderm-produces nervous, epithelial and sensory tissue Mesoderm-skeletal and cardiac muscle, blood and connective tissues Endoderm- organs eg lungs pancreas stomach liver germ cells etc
- Tissue-specific stem cells are maintained in special supportive microenvironments called ???
- Tissue-specific stem cells are maintained in special supportive microenvironments called stem cell niches.
- Supporting ECM
- neighbouring niche cells
- secreted soluble signalling factors (e.g. growth factors and cytokines)
- physical parameters; shear stress, tissue stiffness, and topography),
- environmental signals (metabolites, hypoxia, inflammation, etc.).
Compare the stem cells (table)
What is involved with generatng iPSCs (induced pluripotent stem cells)?
- c-Myc promotes DNA replication and relaxes chromatin structure,
- allows Oct3/4 to access its target genes.
- Sox2 and Klf4 also co-operate with Oct3/4 to activate target genes
- these encode transcription factors which establish the pluripotent transcription factor network
- result in the activation of the epigenetic processes (more open chromatin) that establish the pluripotent epigenome. The
- iPS cells have a similar global gene expression profile to that of ES cells.
Summary of lecture so far
•Stem cells are essential for replacing lost/damaged tissue due to their ability to
self-renew via cell division and the ability to differentiate into many different
cell types
•There are three main stem cell sources: adult (tissue specific stem cells), embryonic stem cells and induced pluripotent stem cells
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•Scientists and doctors can harness the power of stem cells and genetic engineering to provide therapies to replace lost/damaged tissue
What are 2 regeneration strategies looking at cardiovascular complications?
1) Cell transplantation approaches to promote cardiac regeneration and repair, mostly aimed at replenishing lost cardiomyocytes.
Immune rejection, manufacture/isolation of sufficient cells, mode of delivery and clinical regulation all challenges.
2.) Therapies based on direct stimulation of endogenous cardiomyocyte production including re-activation of developmental pathways e.g. epicardium based on models where the is no/reduced scarring and full cardiac regeneration (zebrafish, amphibians, neonatal mice).
What is Myocardial thymosin β4 necessary for?
Myocardial thymosin β4, (Tb4) produced by cardiac mytocytes, is necessary for epicardial migration, coronary vasculature and cardiomyocyte survival
Importantly Tb4 addition to adult hearts can stimulate epicardial outgrowth and neovascualarisation.
Re-expression of a key embryonic epicardial gene Wt1 through priming by Tb4 in vivo. Activated Wt1+ epicardial cells give rise to cardiac progenitors in the MI injured adult heart These can differentiate into de novo cardiomyocytes
Summary of part 2 of lecture
•The adult heart has a low level of endogenous regenerative ability.
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•In the event of an injury such as myocardial infarction scar tissue forms instead of healthy cardiac muscle leading to heart failure
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•Preclinical and initial clinical studies suggest stem cell therapy maybe therapeutic, possibly via direct integration of grafted cells to the myocardium/coronary vessels or by re-expression of developmental gene programmes and paracrine signals which help the host tissue to regenerate
How is stem cell therapy relevant in terms of cancer treatment?
- Chemo/radiotherapy kills cancerous cells. Transplantation of stem cells reconstitutes healthy cells. e.g HSC transplantation for blood cells and leukocytes (lymphoma, leukemia) (ASC, iPSC)
- Clinical trials for other tumour types; brain and breast cancer, neuroblastoma, sarcoma
- Effector immune cells from iPSC/ESCs e.g. engineered T and NK cells targeted for immunotherapy.
- production of anti-cancer vaccines
- MSCs/NSCs deliver genes, nanoparticles, and oncolytic viruses to tumour niche due to intrinsic tumour tropism.
- exosomes extracted from the culture of drug-priming MSCs/NSCs can target the drugs to tumour sites.
- Mutation correction in vitro, drug testing in vitro before replacement in vivo.
Summarise some various types of stem cells that have been identified for use in burns therapy and what they do
- Fetal fibroblasts (from ESCs); improve skin repair due to the high expansion ability, low immunogenicity, and intense secretion of bioactive substances such asFGFs, VEGFs, KGFs
- Epidermal stem cells; high proliferation rate and easy access and keep their potency and differentiation potential for long periods. Generate most skin cell types for repair and regeneration
- Mesenchymal stem cells; They have a high differentiation potential and a certain degree of plasticity. Migrate to the injured tissues, differentiate, and regulate the tissue regeneration by the production of growth factors, cytokines, and chemokines
- iPSCs; can be differentiated into dermal fibroblasts, keratinocytes, and melanocytes.
generally (?)- Replace lost skin cell types, speeding up endogenous healing. Generate ECM and produce paracrine signals which aid healing.
What therapy/information towards therapies has been investigated regarding eye injuries?
What is Retinal pigment epithelium (RPE)?
- Stem cells at the edge of the cornea, limbal stem cells are responsible for making new corneal cells to replace damaged ones.
- If these stem cells are lost due to injury or disease, the cornea can no longer be repaired. This affects the ability of light to enter the eye, resulting in a significant loss of vision.
- Limbal stem cells are collected from an adequately healthy donor eye, and are expanded in the laboratory to sufficient numbers and transplanted into the damaged eye.
- Repairs the cornea and permanently restores vision.
- To avoid immune rejection this treatment only works if the patient has a healthy section of limbus from which to collect the limbal stem cells.
- iPSC cells can be induced to make corneal epithelial cells for transplant and exposure to the right signals can transfor fibroblast cells into limbal stem cells
- Retinal pigment epithelium (RPE) is a single layer of post-mitotic cells, acting as a selective barrier to and a vegetative regulator of the overlying photoreceptor layer,
- RPE has a key role in retina maintenance and parts of the retina can die without a functional RPE leading to loss of vision
- RPE cells can be damaged in a variety of diseases such as: age-related macular degeneration (AMD), retinitis pigmentosa and Leber’s congenital aneurosis.
- RPE cells have been made from both ESC and iPSC
- Several clinical trials for diseases including
age-related macular degeneration (AMD),
retinitis pigmentosa and Leber’s congenital aneurosis show promising results
What has been discovered about Neural stem/progenitor cell grafts? (in relation to spinal cord injury)
- Neural stem/progenitor cell (NSPC) grafts can integrate into sites of spinal cord injury (SCI) and generate neuronal relays across lesions that can provide functional benefit.
- Calcium imaging of NSPC grafts in SCI sites in vivo and in adult spinal cord slices showed NSPC grafts organize into localized and spontaneously active synaptic networks.
- Optogenetic stimulation of host axons produced a neuronal response in the graft and vice versa
- In vivo imaging revealed that behavioural stimulation also
elicited focal synaptic responses within grafts.
•Thus neural progenitor grafts can form functional synaptic subnetworks whose activity patterns resemble intact spinal cord.
What are some conclusions from the last part of this lecture that can be made?
- Preclinical and clinical trials are on-going for a wide variety of stem-cell based therapeutic approaches
- In cancer, stem cells can be used repopulate the body with healthy non-malignant cells and genetic engineering of stem cells can produce cells with anti-cancer properties.
- Transplantation approaches are providing positive results for eye diseases, burn wound healing and spinal cord injuries
- Many other stem-cell based therapies are currently being developed for different tissues and diseases
