Stem Cells and Ageing

Ageing

• progressive loss of physiological integrity in the entire body which leads to impaired function and increased vulnerability to death

• this deterioration is the primary risk factor for major human pathologies

Stem cell ageing

• stem cells become exhausted and there is a loss of regeneration

What is a stem cell

• a single cell that can replicate itself or differentiate into many cell types

Differentiation

• the process by which cells become increasingly specialised to carry out specific functions in tissues and organs

Potency

• the ability of stem cells to differentiate into specialised cell types.

• potency varies between different types of stem cells

• cells with the greatest potency can generate more cell types than those with lower potency

Totipotent cells

• give rise to all cell types of the body as well as extra-embryonic cells (placenta)

• can form a complete organism

Pluripotent stem cells

• can give rise to all cell types of the body(but not the placenta)

• CANNOT form a complete organism

Multipotent stem cells

• multipotent stem cells develop into a limited number of cell types in a particular lineage

Symmetric and Asymmetric Cell Division

Symmetric

• stem cell divides into two copies of itself

Asymmetric

• stem cell divides into a copy of itself and a differentiated progeny

Embryonic Stem (ES) Cells

• derived from the undifferentiated inner mass cells of a human embryo (extracted by using powerful scientific and medical tools)

Properties:

• Pluripotent

• Replicate indefinitely (immortal)

Embryonic stem cells as a tool

• can become any cell type therefore if we control their differentiation we can create tissues for use in regenerative medicine (like forming new organs)

• can direct stem cells to form damaged cells to replace them

• useful for spinal cord injuries, type 1 diabetes, parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, stroke, burns, cancer, osteoarthritis, heart disease and etc

Ethical concerns of embryonic stem cell usage

• to get embryonic cells you need a human embryo thus is this destroying a life and when does life begin?

Reprogramming somatic cells

• proven in 2006 in mice and 2007 in humans

• these cells are called induced pluripotent stem cells

Advantages of IPS cells

Properties:

• pluripotent

• replicate indefinitely

AND:

• no embryo needed thus no ethical issues

• there is potential for immuno-compatible regenrative medicine (patient specific IPS cells)

How human IPS cells are formed?

• an adult cell is taken (normally skin or buccal cells)

• add reprogramming factors which are genes active in ES cells

• cell switches from adult cell to stem cell, changes in shape, gene expression and chromatic structure is observed

• no resemble ES cells

• can differentiate these cells into any other cell type

What can we do with IPS cells?

• huge medical potential which is moving at such a rapid rate and it is impossible to review all applications it has been used for

• at least 50 different diseases have been modelled with IPS cells

Cons of IPS cells

• still a very new field thus still a lot to learn about the potential and use

• can form tumours more than ES cells thus posing a major obstacle to stem-cell based regenerative medicine

• genes we use to create iPSC also linked to cancer in one way or another

• shown to illicit a greater immune response than ES cells

Stem cell continuum

Somatic/adult stem cells

Properties:

• multipotent

• replicate indefinitely (immortal)

AND:

• found among differentiated cells in a tissue or organ

• found in specific areas in each tissue (stem cell niche), various different niches all over the body

• no embryo destroyed to make them - from adult tissues and can be patient specific

• the stem cells that are responsible for stem cell ageing

what else goes into a niche

• the surrounding environment is crucial to their survival and ability to function

• the niche is highly dynamic microenvironment adapts to physiological or diseased conditions

• niche regulates how stem cells participate in tissue generation, maintenance and repair.

• Prevents stem cell depletion - and stops overproduction of stem cells.

Adult stem cell niches - intestine

• ISC - intestinal stem cell

• present at the base of a glandular crypt

• give rise to TA (transit-amplifying) cells - migrate upwards to replace cells on surface

• from ISC in crypt to tip of villus is 3-5 days

Adult stem cell niches - bone marrow

• bone marrow contains 2 stem cell niches

• hematopoietic stem cells - give rise to all components of the blood and immune system (important part of a bone marrow transplant)

• mesenchymal stem cells - make cartilage bone and fat

Bone marrow transplants

• a well known form of stem cell therapy

• hematopoietic stem are the major components in a bone marrow transplant - collect them from peripheral or cord blood stored umbilical cord blood

• function: after high doses of chemotherapy or radiation, rescue the bone marrow damaged by treatment, restore immune function replace diseased or damaged marrow with new stem cells

Mesenchymal Stem Cells

• found in bone marrow - also part of bone marrow transplants, cord blood or adipose tissue amongst others

• can form a variety of tissue types - multipotent

• modulate immune responses - mean less chance of rejection

• can treat immune disease as well as used in tissue regeneration

Umbilical cord stem cells

• a host of companies now sell storage of your new-born’s umbilical cord blood when needed can you can get blood out of cold storage

• can be used to reconstitute bone marrow, to treat various blood cancers and forms of anaemia

• is just as effective as bone marrow transplant but stem cells are younger

Limitations of umbilical cord stem cells

• Not many stem cells in cord blood ( fewer than bone marrow) and not much material. One umbilical worth of blood often not sufficient for an adult

• Irreplaceable

• Only get haematopoietic stem cells – other stem cell types claimed by companies are unproven in therapeutic use.

• Costly to store

Stem Cell Hypothesis of Ageing

• stem cells repair and replenish damaged tissues throughout life

• these are adult stem cells in their various niches

• function of stem cells declines with age - undergo age-related damage

• stem cells lose ability to self-renew and lose differentiation ability

• stem cell theory of ageing postulates that aging is NOT a matter of the increase in deterioration of tissues - but a failure to replenish tissues due to a decreased number and decreased function of resident stem cells

• Ageing of stem cells mirror ageing of other tissues –inflammatory responses, stress responses, and substantial alterations in the regulation of chromatin structure

Impact of ageing on adult stem cells

genetic and epigenetic changes in ageing stem cells

• Many reports of unstable genomes in older stem cells. – DNA damage accumulates

• Lines of evidence

  • Mice with defects in DNA damage repair display

  • some aspects of premature ageing

  • Enhancing DNA repair increases lifespan

  • Marker of DNA damage present in aged stem cells

Telomere shortening

• Happens to all cells during DNA replication

• Also happens to stem cells

• Causes a stop in cell division- stop in self-renewal – stem cell failure

Cell cycle activity in stem cells with age

• in aged mice HSCs have decreased cell cycle activity

• Old HSCs undergo fewer cell divisions than young ones

• Increase in factors that inhibit the cell cycle

• ALSO - excessive proliferation is deleterious.

• More the cells divide – the faster they age – this leads to premature exhaustion

Ageing hematopoietic stem cells

• Functional attrition of stem cells found in all adult stem cell compartments

• Haematopoiesis declines with age due to exhausted stem cells.

• Diminished production of immune cells— immuno-senescence.

• Increased incidence of anaemia and myeloid malignancie

Ageing hematopoietic stem cells

Ageing Mesenchymal stem cells

• isolating from bone marrow aspiration shows decline in MSC numbers with donor age.

• older MSCs also show reduced proliferative capacity and reduced potential to form bone

• enter cell cycle arrest (senescence)

Agening skin stem cells

• Skin has different types of stem cells

  • Hair follicle stem cells (HFSC) sustain hair growth

  • Epidermal stem cells replenish skin

  • Melanocyte stem cells generate pigment producing cells

  • Dramatic reduction in melanocyte stem cells numbers with age – visible effect in people

  • HFSC – DNA damage causes loss of stem cell and eventually loss of hair follicle entirely

HSFC

• Epidermal stem cells – reduced number with age - Impaired wound healing

• HFSC – DNA damage causes loss of stem cell and eventually loss of hair follicle entirely

Ageing Skeletal Muscle Satellite (Stem) Cells

• small population of quiescent stem cells

• mobilised in response to injury

• Age-related Changes:

  • Number of satellite cells decreases with age – loss of cell renewal

  • Regeneration potential on transplantation declines with age

  • Ability to replenish damaged muscles severely reduced

  • Recover from muscular injury is effected

Ageing neural stem cells

• Adult neural stem cells (NSCs) present in some different brain regions - mediate local neurogenesis and brain functioning Ageing stem cells - decreased neurogenesis - advent of related ageing-associated disorders Reduction in neurons over time causes brain shrinkage - loss of efficacy

• Hippocampus – major source of adult NSCs is crucial for memory and learning as well as ageing in general.

• NB: neurons produced in hippocampus throughout adulthood, new studies prove this but still drop in quality of these new neurons with stem cell ageing

• Ageing stem cells - decreased neurogenesis - advent of related ageing-associated disorders

• Reduction in neurons over time causes brain shrinkage - loss of efficacy

Stem cell transplants as anti-ageing treatment

• ageing stem cells causes deterioration of the body - transplanting young stem cells to cause recovery

• progeria - abnormal rapid ageing, loss of muscle mass, difficulty moving, trembling

• systemic effects cause by secreted factors from transplanted stem cells

Stem cell transplants - curing blindness

• age-related macular degeneration: common form of blindness

• deterioration of central part retina - responsible for focusing vision incurable

• using embryonic stem cells - differentiated them into RPE (retinal pigment epithelium) - embed onto scaffold transplant them onto the retina - restores vision

• in future will use IPS cells and remove ethically quadary

Stem cell transplants - slow brain ageing

• neural stem cells injected (replacing those in hippocampus) which makes new neurons ageing slowed

• NSCs release molecules called miRNAs - helped maintain a youthful status lost over time and with age

• currently working on investigating in humans

Rejuvenating stem cells

• Instead of replacing ageing stem cells can we rejuvenate them?

• Hints from iPSC – have reprogrammed adult cells – give clues about resetting chronological age

• Has been found that during iPSC reprogramming can reactivate telomerase (enzyme that extends telomeres)

• BUT - emphasis of research in the field of reprogramming is not on reversing ageing. Reversal of the differentiation – attaining pluripotency is goal

• In addition – we can make cells pluripotent – this is NOT reversing ageing – might be dangerous

Parabiosis

• two animals share a common bloodstream

• Current parabiosis research focuses on if adult stem cell rejuvenation occurs in a young environment

• Old mice stronger, smarter and healthier. It even makes their fur shinier – Stem cells are rejuvenated

• Question remains if it is de -ageing – or just restoring function to damaged tissues ?

• ALSO – Paired young mice AGE. Stem cells have an aged molecular and functional state.

• Systemic environment determines functional age – cost to this procedure