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Molecular basis of disease > Stem Cells and Regenerative Medicine > Flashcards

Stem Cells and Regenerative Medicine Flashcards

1
Q

What are stem cells?

A
  • Can differentiate into many different cell types depending on the types of signals received.
  • 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.
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2
Q

What are potential uses of stem cells?

A
  • Stroke
  • Baldness
  • Blindness
  • Myocardial Infarction
  • Cancers
  • Spinal cord injury
  • Wound healing
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3
Q

What are Adult Stem Cells (ASCs)?

A
  • Rare but replace dead or damaged cells.
  • These are multipotent and tissue specific.
  • Scientists can take these and amplify and manipulate them in vitro allowing us to use them for a variety of purposes.
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4
Q

What are Embryonic Stem Cells (ESCs)?

A
  • Supply all cells of developing embryo and are pluripotent.
  • Derived from embryos at blastocyst stage before implantation.
  • Stem cells reside in inner cell mass. ESCs can develop into any of the 3 embryonic germ layers (ectoderm, endoderm, mesoderm).
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5
Q

What are Induced Pluripotent Stem Cells (iPSCs)?

A
  • They are made in the lab and can be reprogrammed by specific exposure to a set of pluripotency factors. E.g OCT4, SOX2, KLF4 to produce iSPCs with similar characteristics to ESCs.
  • These can be used for cell therapy repairing mutations using gene manipulation techniques e.g CRISPR and differentiating them in vitro and back to the patient.
  • Cells are specific to the patient and reduce rejection by the host.
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6
Q

What are other uses of stem cells?

A
  • Model for basic and translational studies
  • Disease modelling
  • Drug screening
  • Cell replacement therapy
  • Cell differentiation
  • 3D organoid models
  • Developmental biology
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7
Q

Where are stem cells maintained?

A
  • stem cell niches
  • Niches interact with stem cells to regulate cell fate and protect stem cells from depletion and the host from excessive proliferation.
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8
Q

What is the comparison of stem cell types?

A
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9
Q

What are the features of stem cell niches?

A
  • Supporting ECM
  • Neighbouring niche cells
  • Secreted soluble signaling factors (e.g growth factors and cytokines)
  • Physical parameters (e.g shear stress, tissue stiffness and topography)
  • Environmental signals (metabolites, hypoxia, inflammation etc)
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10
Q

What are the advantages and disadvantages of ESCs?

A
  • Advantages
    • Pluripotent - almost unlimited growth potential - may differentiate into any kind of cell
    • Unlimited numbers of cells due to high cell potency
    • Very low probability of mutation induced damage in the DNA
  • Disadvantages
    • Higher risk of tumour creation
    • Risk of being genetically different from the recipient’s cells - higher risk of rejection
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11
Q

What are the adv and disadv of ASCs?

A
  • Advantages
    • Compatible with recipients cells - low risk of rejection
    • Less risk of tumour creation
  • Disadvantages
    • Oligopotent - unipotent - limited cell potency
    • Limited numbers may be obtained
    • Higher probability of mutation-induced damage in the DNA - risk of dieases
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12
Q

What are the adv and disadv of iPSCs?

A
  • Advantages
    • Compatible with receipient’s cells - low risk of rejection
    • Less risk of tumour formation
  • Disadvantages
    • Less growth potential than ESCs
    • Rather limited numbers may be obtained
    • Higher probability of mutation-induced damage in the DNA - risk of diseases.
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13
Q

How do you generate iPSCs?

A
  • 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.
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14
Q

What is stem cell tracking?

A
  • Stem cells can be manipulated by in vitro to make them easier to track once implanted in vivo.
  • Insert a reporter gene e.g make cells fluorescent.
    • Track where stem cells go and how they behave after being inserted into a model e.g patient
  • In vivo imaging can aid the development and clinical translation of cell-based therapeutics using non-invasive in vivo long-term cell tracking in the preclinical and clinical settings.
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15
Q

What is one of the least regenerative organs in the body?

A

The heart is one of the least regenerative organs in adult humans, making it difficult to repair damage caused by injury/disease.

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16
Q

Why is the heart not regenerative?

A
  • During a heart attack blood supply to heart muscle is lost. Cardiac muscle dies and is not replaced, as adult cardiomyocyte turnover is low. Instead there is often fibrosis and scarring leading to decreased cardiac function and heart failure as the heart is stiff and slow.
  • Research into therapies to replace lost cardiac muscle and improve blood supply to the affected region is a high priority.
    • Relevant for cardiomyopathies and conduction defects.
17
Q

What do heart diseases cause?

A
  • Cardiovascular disease causes >25% UK deaths, 1 in every 3 minutes. Cost is 19 billion/year.
  • Coronary heart disease is the UKs biggest single killer. Even if you survive a heart attack (70% do) the chance of developing heart failure as a result is high.
18
Q

How is neovascularisation a regeneration strategy?

A
  • Promoting neovascularisation through implantation of stem cells to develop into new coronary vessels or by cell free methods is important for cardiomyocyte regeneratio
  • Improved circulation to injured area
  • Paracrine effects improving CM replacement
19
Q

What are cell-based therapies?

A
  • 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.
20
Q

What are cell-free therapies?

A
  • Therapies based on direct stimulation of endogenous cardiomyocyte production including re-activation of developmental pathways
    • e.g epicardium based on models where this is the no/reduced scarring and full cardiac regeneration (Zebrafish, amphibians, neonatal mice).
21
Q

What do we see in animals that regenerate their heart?

A

We see re-expression of developmental gene program early after the injury such as Wt1. These programs are found in the epicardium.

22
Q

Why is the epicardium important?

A
  • Epicardium is an important source of cells for coronary vessels and signals which promote cardiomyocyte proliferation.
  • Epicardial activation is followed by activation of the endocardium. Cardiomyocyte dedifferentiation, formation of a fibrin clot which degrades as cardiomyocytes proliferate and regenerate the heart.
23
Q

What happens in larger animals during cardiomyocyte regeneration?

A

In larger animals, a fibrin clot does not dissolve and forms a fibrotic scar that effects cardiac function. E.g pigs and primates.

24
Q

How has research shown that immune and lymphatic responses to injury are important in cardiac regeneration?

A
  • In regeneration of neonatal mouse hearts, there is infiltration at the injury of embryonic macrophages, revascularization and global cardiomyocyte proliferation.
  • In adults there Is infiltration by monocyte derived macrophages, limited revascularization and no cardiomyocyte proliferation.
  • In a normal injury response, lymphatic does not clear excess tissue fluid leading to oedema and inflammation which produces poor cardiac repair and function.
  • If lymphatic system is stimulated with a modified form of VEGFC there is an increased lymphatic response which improves cardiac repair and function.
25
Q

How do you make cardiac lineages from iPSC cells?

A
  • Somatic cells are reprogrammed to iPSCs then specified with pre cardiac mesoderm which acts as a downstream switch for number of signaling factors including Wnt signaling → differentiation of cardiac progenitor cells.
  • Provision of specific signalling molecules further differentiate these cells to cardiac lineages.
    • E.g epicardial cells, cardiac fibroblasts, cardiomyocytes, smooth muscle cells etc.
26
Q

What is an example of allogenic transplantation of iPS cell-derived cardiomyocytes regenerated primate hearts?

A
  • Monkey model (Macaca fascicularis) has identical MHC structure to humans
  • Fibroblast-derived iPSCs made from a MHC haplotype (HT4) homozygous animal were differentiated into cardiomyocytes
  • Grafted cardiomyocytes (GFP+) survived for 12 weeks with no evidence of immune rejection. showed:
    • Electrical coupling with host cardiomyocytes
    • Improved cardiac contractile function at 4 and 12 weeks after transplantation
27
Q

What is an example of stem cell transplantation using ESC-derived cardiomyocytes restore function in infarcted hearts of non-human primates?

A
28
Q

What is developmental gene reactivation?

A
29
Q

What is an example of transplantation and paracrine signals?

A
30
Q

What do preclinical and clinical studies suggest about stem cell therapy?

A

It may be 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

31
Q

What is stem cell-based therapy for cancer?

A
  • Chemo/radiotherapy kills cancerous cells. Transplantation of stem cells reconstitutes healthy cells. e.g HSC transplantation for blood cells and leukocytes.
  • 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
32
Q

How is stem cell therapy used for burns?

A
  • Replace lost skin cell types, speeding up endogenous healing. Generate ECM and produce paracrine signals which aid healing.
    • Fetal fibroblasts - from ESCs improve skin repair due to high expansion ability, low immunogenicity, intense secretion of bioactive substances FGFs, VEGFs, KGFs
    • Epidermal stem cells - high proliferation rate, easy access, high potency and differentiation. Generate most skin cell types for repair and regeneration
    • Mesenchymal stem cells - high differentiation potential and plasticity. Migrate to injured tissues, differentiate, and regulate the tissue regeneration by the production of growth factors, cytokines and chemokines.
    • iPSCs - can differentiate into dermal fibroblasts, keratinocytes, and melanocytes.
33
Q

How does stem cell therapy for burns start?

A

Isolation and production of stem cells and amplification of required phenotypes in culture. Cells can be selected due to a variety of factors e.g secretion of growth molecules.

34
Q

How are cells delivered to patients by a variety of methods?

A
  • Dressings
  • Cell sprays onto the wound
  • 3D printing of cell sheets
35
Q

What is stem cell-based therapy for eye injury/disease to repair the cornea?

A
  • 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 - affects light entering the eye → loss of vision
  • Limbal stem cells are collected from healthy donors, expanded in numbers and transplanted into a damaged eye.
  • Repairs cornea and permanently restores vision.
36
Q

How do stem cells repair the retina?

A
  • Retinal pigment epithelium (RPE) is a single layer of 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 functional RPE → loss of vision
  • RPE cells can be damaged by age-related macular degeneration (AMD), retinitis pigmentosa and Leber’s congenital aneurosis.
  • RPE cells made frmo both ESCs and iPSCs.
37
Q

How are stem cells used for spinal injuries?

A
  • Take adult stem cells from patient, transform these into iPSCs via reprogramming factors and differentiate into neural stem cells and differentiate at the site of the spinal injury.
  • Neural stem/progenitor cell (NSPC) grafts can integrate into sites of spinal cord injury and generate neuronal relays across lesions.
  • Neural progenitor grafts can form functional synaptic subnetworks whose activity patterns resemble intact spinal cord.
38
Q

What are positive outcomes of stem cells in clinical trials?

A
  • 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

Molecular basis of disease (31 decks)

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