repro 2

Infertility

-        Inability to conceive after 12 months in women under 35 or 6 months in women over 35, of having sexual intercourse with average frequency without the use of any form of birth control

-        Average incidence of infertility ~15% globally

-        Unexplained infertility constitutes ~10% of all cases

-        About 1in 9 couples in Australia will struggle to get pregnant at some point

contraceptives

-        Use of contraceptives directly influences fertility rate

-        Hormonal

o    Prevent ovulation

o    Change cervical mucus to make it impenetrable to sperm

o    Slow down/kill sperm

o    Reduction of endometrial lining

o    Interference with implantation

-        Barrier dependent:

o    Physical barrier between semen and vagina/uterus

o    eg: diaphram, condom, sponge spermicides

The “Oral contraceptive pill”

-        Taken daily & at the same time -> ensure constant hormone levels -> not effective if diarrhea or vomiting

-        Contains synthetic analogs of estrogen, progestin or mix

- negative feedback to hypothalamus and anterior pituitary -> less production of FSH and LH -> Inhibited follicle maturation in female ovaries -> Progesterone prevents LH surge -> no ovulation

-        Thins uterine lining

-        Progestin (Progesterone) thickens cervical mucus

-        Side effects can include moodiness, headaches, nausea, blood clots (estrogen), heart attack & stroke

-        During placebo pills of package estrogen and progesterone in blood will fall –> LH and FSH will be produced by anterior pituitary –> follicles will start to mature –> after ~2 days progesterone levels low enough for menstruation to occur

Plasma concentration profile of chemicals taken orally

-        With oral intake of chemicals at first spike in plasma drug levels

-        Drug levels in plasma then decline over time

-        Drug becomes ineffective at the suboptimal plasma concentration -> a second tablet has to be taken

-        Enough dosage has to be administered to reach therapeutical effective levels, without causing toxicity.

-        Most drugs coated/in capsules & chemically modified -> get reabsorbed slower but also maintain their effective levels longer

The “mini-pill”

-        Contains only synthetic progesterone

-        taken continuously without any breaks

-        Thickens cervical mucus -> prevents passage of sperm into uterus

-        May prevent ovulation

-        Thins endometrial lining so no implantation

-        Usually no menstruation (high progesterone)

Depot contraceptive chemicals

-      A hormonal injection given every 12-13 weeks to prevent pregnancy.

- It uses the progestin hormone to stop ovulation, thicken cervical mucus, and thin the uterine lining

- Depot chemicals aim to have therapeutical drug level maintained

-        Less fluctuation of chemical levels in blood

Copper Intrauterine devices (IUDs)

-        >10 years

-        Interferes with sperm, fertilization and prevents implantation

-        Side effect: heavy or irregular menstruation

hormonal IUD

-        Plastic T shaped hormone reservoir

-        Releases synthetic progestin

-        Changes cervical mucus

-        Reduced uterine lining

-        Stops or slows sperm and oocyte

-        >5 years

-        Can be removed at any time

-        Side effect: missed periods (amenorrhea)/little menstruation, spotting

Female sterilization: Female tube ligation

-        Fallopian tubes blocked, clipped or shut -> prevents sperm reach oocyte -> prevents oocyte from reaching uterus

-        Oocytes in fallopian tube reabsorbed by body

vasectomy

-        Vas deferens is sealed, tied or cut

-        After vasectomy ejaculation possible but semen without sperm

-        Sperm produced but cannot leave testes -> sperm deteriorates and gets phagocytosed/degraded

-        Testosterone still produced – sex drive normal, male sex characteristics

Temperature methods

-        Before ovulation, during follicular phase, basal temperatures low

-        After ovulation, when there is increased progesterone secreted from the corpus luteum, temperatures become very slightly elevated

-        Can detect the difference between pre-ovulation and post-ovulation temperatures when they are plotted on a graph

-        Temperature will drop if fertilization does not occur

Calendar method/Rhythm method

-        Estimate fertile and infertile days based on previous menstrual cycle

-        The fertile window includes the five days leading up to ovulation, plus the day of ovulation itself, and the day after.

o    Timing of ovulation can vary by several days even in regular cycles

o    Sperm can typically stay alive for ~3 - 5 days within the cervix, uterus and fallopian tubes.

Male hormonal contraception studies

-        Currently none approved yet

-        Initial studies focused on intramuscular administration of Testosterone enanthate (TE)

o    suppression of spermatogenesis

o    suppression of sperm concentration to very low levels -> azoospermia (semen contains no sperm) or severe oligospermia (low sperm count)

o    common side effects: acne, altered libido, night sweats, increased weight, and mood changes

Male Hormonal changes during a lifetime

-        Before puberty: Testosterone levels are low.

-        Puberty: Testosterone production surges, leading to the development of male secondary sexual characteristics.

-        Peak Testosterone: Testosterone levels typically peak in the late teens and early twenties ->remain high for the next two to three decades

-        With age, testosterone levels drop about 1% per year starting in men’s 30s and 40s.

-        Rate of decline in testosterone levels varies in different individuals and can be affected by chronic disease, excess weight, illness, serious emotional stress, and medication side-effects

Female Hormonal changes during a lifetime

-        Before puberty: Estrogen and progesterone levels are low.

-        Puberty: Estrogen and progesterone levels rise, triggering development of secondary sex characteristics (pubic hair, breast growth, menstruation)

-        Reproductive Years: Estrogen and progesterone levels fluctuate cyclically

-        Pregnancy: Estrogen & progesterone, increase significantly to support developing fetus.

-        Menopause: Ovaries cease to produce estrogen and progesterone -> levels decline and cessation of menstruation

onset of puberty

-        HPG-axis is active during fetal development and the first few months of life but suppressed in infancy by neural input to the arcuate nucleus and remains so throughout childhood (juvenile pause)

-        Pubertal onset is initiated by reactivation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion, which then regulate reproduction, reproductive behaviors and secondary sexual characteristics, and sex steroid levels

-        Puberty: Stage during which people reach full reproductive ability and develop the adult features of their sex

-        May begin as early as age 9 and continue until ~ age 16

The role of kisspeptin

-        Neuropeptide with critical role in the function of the HPG axis

-        Kisspeptin regulates the release of GnRH from the hypothalamus

-        Gonadal sex steroids stimulate a specific group of kisspeptin neurons in a positive feedback mechanism and block other kisspeptin neurons in negative feedback respectively

-        With beginning of puberty, nerve cells in the hypothalamus produce and release Kisspeptin, Dynorphin and Neurokinin B =KNDy

-        These three proteins act in together to induce the release of GnRH in a pulsating manner

-        Excess activity of kisspeptin due to genetic differences can cause early puberty = precocious puberty

-        Lack of kisspeptin can cause hypogonadotrophic hypogonadism (insufficient GnRH -> insufficient LH and FSH - > lack of testosterone (men) or oestradiol (women)

The ovarian reserve

-        Ovary establishes 6-7 million non-growing follicles at ~ 5 months of gestational age

-        Follicles decline with increasing age culminating in the menopause at 50–51 years

-        Progressive decline in follicles is attributed to follicular atresia by apoptosis

-        Studies estimate that at age 30 only 12% if follicles remain, at age 40 only 3% remain (for 95% of women)

-        Menopause occurs when number of ovarian follicles is reduced to a critical threshold

The ovarian reserve measures

-        Anti-Mullerian hormone (AMH) is produced by granulosa cells in the developing follicles in the ovaries

-        AMH levels are highest after birth and decline with age

-      Levels indicating possible health problems:

-        below 1 ng/mL: (possible fertility issues)

-        >4 ng/mL: could indicate PMOS)

Menopause 3 stages of hormonal changes with age:

Perimenopause:

-        Begins with irregular menstrual cycles due to declining ovarian function (ovaries make less estrogen)

-        Average duration is three to four years

Menopause:

-        Defined retrospectively when menses have ceased for an entire year (no more ovulation)

-        Age at menopause genetically determined ~50-55 years

-        No further follicle development or ovulation -> infertility

-        Ovaries stop estrogen and progesterone production (instead, fat cells start making majority of body’s estrogen) Note: Progesterone also produced by adrenal glands

Postmenopause: All years after menopause

Menopause Treatment

Hormone replacement therapy (HRT) (Estrogen-progesterone preparations)

-        available as tablets, patches, gels or vaginal treatments

-        some HRT regimens include testosterone to improve wellbeing and sexual function

o    Common treatment for low estrogen, especially during menopause and postmenopause

o    Synthetic forms of estrogen and/or progesterone given to boost levels

o    Two types of HT: Estrogen therapy and estrogen progesterone/progestin hormone therapy (EPT). ● Providers prescribe the lowest doses possible to treat symptoms while preventing side effects

The Male climacteric - symptoms

-        Male climacteric associated with decline in testosterone levels with age

-        Symptoms: Depression nervousness, Flushes and sweats, Decreased libido, Erectile dysfunction, Tiredness, Poor concentration and memory, Declining sperm production and motility

Average testosterone levels in men

-        Total testosterone in blood in men (both bound and unbound testosterone): 7.6 - 31.4 nmol/L. Total testosterone falls ~1.6% on average/year

-        Free testosterone in blood in men: ≥0.3 nmol/L; Free testosterone falls by 2 to 3%/year

-        Often accompanied by loss of muscle mass, accumulation of central adiposity, impaired mobility and increase risk of bone fracture

Congenital Defects = birth defects = congenital anomalies = congenital disorders

-        Refer to all inborn abnormalities, morphological or biochemical present at birth

-        ~50-80 % of conceptuses lost before implantation

-        Investigated miscarriages >50% due to chromosomal structural abnormalities

-        ~2% of all pregnancies terminate in stillbirths (20-25% exhibit serious anomalies at autopsy)

-        Congenital defects found in 6% of all liveborn infants examined during the first year of life

-        ~ 1.3% of all infants die within the first year of life (25-30% reveal congenital defects)

Causes of Congenital Defects

-        Idiopathic (majority)

-        Multifactorial

-        Environmental factors

• Infectious Agents

• Chemical & Pharmacological

• Radiation

-        Genetic defects

• Chromosomal

• Monogenic

Teratogens:

Any environmental agent that can harm an embryo or fetus = any agent or substance that can cause embryonic malformations or birth defects

impact depends on: Dosage and duration of exposure of drug/chemical, Critical period of development

Embryonic sensitive periods: CNS, H, A, L, EYES, T, P, EG, EARS

-        CNS: 3-16 weeks

-        Heart: 3-6 weeks

-        Arms: 4-5 weeks

-        Eyes: 4-8 weeks

-        Legs: 4-6 weeks

-        Teeth: 6-8 weeks

-        Palate: 6-9 weeks

-        External genitalia: 7-9 weeks

-        Ears: 4-9 weeks

Infectious agents - Rubella

-        Infectious viral disease

-        Congenital rubella syndrome -> miscarriage or birth defects including heart defects, deafness, brain damage, eye problems, cardiac abnormalities, mental retardation

-        Most dangerous during 1st trimester (40-60% chance of affected fetus)

Infectious agents - Toxoplasmosis

-        A zoonotic intracellular parasitic infection caused by Toxoplasma gondii (a protozoan)

-        Caused by eating undercooked/contaminated meat, handling cat feces

-        Can cross the placenta -> can affect the brain e.g. hydrocephalus, mental retardation and impaired vision & blindness, during first trimester

-        Induces miscarriage later in pregnancy

Infectious agents – Zika virus

-        Zika virus can be transmitted from mother to fetus during pregnancy

-        Congenital Zika syndrome: Infection during pregnancy -> can cause infants to be born with microcephaly and other congenital malformations

-        Zika infections in pregnant women also have been linked to miscarriages and stillbirth

-        In CT scans of infants -> calcifications in brain tissue

Listeria bacteria -> infection called listeriosis

-        Pregnant women advised not to eat any uncooked mould-ripened soft cheese (brie, camembert), raw seafood (oysters, sashimi, sushi), smoked ready-to-eat seafood and cooked ready-to-eat prawns

-        Listeria infection during pregnancy can cause miscarriage, stillbirth or severe illness in newborns

Salmonella: Salmonella bacteria -> can cause gastroenteritis or food poisoning

-        Avoid foods that contain raw and undercooked protein -> eggs or reheated chicken

-        Risk for unborn much lower compared to listeria

- potentially leading to miscarriage, preterm labor, or severe newborn infections like sepsis and meningitis

Chemical & Pharmacological Teratogens Thalidomide 1950-1960:

-        Can cause severed birth defects if taken during first 2 months of pregnancy

o    Phocomelia: fetus with hands and feet without arms or legs

o    Ectromelia: total absence of limbs

o    Malformation of eyes, ears, noses, hearts, thumbs

Chemical & pharmacological teratogens Folic acid deficiency

-        Neural groove closes in week 4 -> failure of the neural tube to close anywhere along its length = neural tube defect

-        Known association between low folic acid, maternal insulin dependent diabetes, and maternal use of certain anticonvulsant medications

-        Low maternal dietary folate associated with development of neural tube defects ➢Folic Acid (Folate)= vitamin B9

Chemical & pharmacological teratogens Neural tube defects:

-        Anencephaly: total or partial absence of cranial vault, brain and the covering skin

-        Spina bifida: affects the backbone & sometimes spinal cord, e.g. dorsal malclosure of vertebrae, surgical repair after birth

-        Encephalocele or Meningocele: may contain herniated meninges and brain tissue

Chemical & pharmacological teratogens 29 Alcohol

-        Compromises functioning of the placenta

-        Can easily cross placenta -> adversely affects fetal development

-        Chronic alcohol abuse can result in fetal alcohol syndrome (30-45%) Fetal alcohol syndrome (FAS) Microcephaly, malformation of heart, limbs, joints and face, hyperactivity, seizures, tremor, lower IQ, major adjustment problems, slow physical growth, poor motor skills, attention difficulties, verbal learning difficulties

Radiation in pregnancy

-        Death, mental retardation

-        Severity differs depending on stage of pregnancy (organogenesis) and absorbed dose

-        Chernobyl radiation accident in 1986, Atomic bomb explosion over Hiroshima & Nagasaki -> 25 % of surviving children born with CNS abnormalities (microcephaly & mental retardation)

-        Relative risk of leukaemia and cancer may be as high as 1.4 -> Avoid X-rays during pregnancy

Inborn errors of metabolism

Any rare disorder caused by an inherited genetic defect in metabolism

Incidence of inborn errors of metabolism ~ 1: 4,000 live births

-        Usually autosomal recessive

-        >500 diseases known

-        Can result in injury to any tissue, but most damage to developing brain

-        Mainly represent as reduced activity/ complete absence of enzymes in biochemical pathways:

Inborn errors of metabolism: Encephalopathy

-        Overarching term for accumulation of an otherwise normal metabolite that becomes toxic when present in excess concentration in the brain

Inborn errors of Amino acid metabolism Phenylketonuria (PKU)

-        Autosomal recessive, Chromosome 12

-        Liver enzyme phenylalanine hydroxylase missing

-        ~1:5,000 - 10,000 births

-        Phenylalanine is obtained through the diet (mainly proteins)

-        Conversion of amino acid phenylalanine to tyrosine is disrupted

-        If untreated built up of phenylalanine in the blood & harm central nervous system

-        Treatment: phenylalanine restricted diet

Inborn errors of Carbohydrate metabolism Galactosemia type I

-        Autosomal recessive

-        Mutations in the GALT gene -> Body unable to metabolize the simple sugar galactose -> inability to use galactose to produce energy

-        Affects 1:30,000 to 60,000 newborns

Inborn errors of Lipid metabolism Tay-Sachs

-        Autosomal recessive

-        Enzyme Hexosaminidase A missing

-        Mutation in HEXA gene on chromosome 15

-        Lipid storage disorder

-        Symptoms: hearing loss, seizures, physical and mental retardation, dementia, red dots on retina

Inborn errors of Protein metabolism Hemophilia

-        X-linked recessive

-        Absence of clotting factors in plasma

-        1 in 5,000 live male births

-        Blood clotting occurs in a cascade

-        Any factor insufficiency in the cascade can lead to insufficient blood clotting

Inborn errors of Pigment metabolism Albinism

-        Autosomal recessive

-        Defective enzyme: tyrosinase

-        Complete absence of melanin synthesis

-        1:20,000 births

-        Hair white, blue eyes, skin UV sensitive

-        Abnormal development of the retina and abnormal patterns of nerve connections between the eye and the brain – vision problems

Mutant Genes - Achondroplasia

-        Form of short-limbed dwarfism

-        Two specific mutations in the FGFR3 gene are responsible for almost all cases

-        Average height of adult male: 131cm (4 feet, 4 inches)

-        Average height of adult female: 124 cm (4 feet, 1 inch)

-        Most common form of short limb dwarfism:

o    occurs in 1 : 15,000 to 40,000 newborns

-        Autosomal dominant ~80 percent have average-size parents; these cases result from new mutations

Polydactyly

-        Person born with extra fingers or toes

-        Results from defective patterning of the anterior- posterior axis of the developing limb

-        Full range of Mendelian inheritance patterns

-        Small finger duplication is often hereditary

-        100 genes identified that can lead to polydactyly

Autosomal Dominant – Huntington’s disease

-        Affects ~ 1:20,000, chromosome 4

-        Expansion of a cytosine-adenine-guanine within Huntingtin gene -> altered expression of the protein huntingtin -> variable severity depending on (CAG) repeat number

-        Mutated protein increases decay rate of certain types of neurons

-        Symptoms: chorea = jerky, and uncontrollable movements

Autosomal Recessive - Cystic Fibrosis (CF)

-        Affects ~1:2500 in Australia

-        Chromosome 7 transmembrane conductance regulator gene (CFTR) ➢CFTR= Membrane channel in cells that produce mucus, sweat, saliva, tears, digestive enzymes

-        Intact CFTR usually helps to move NaCl out of cells -> defective CFTR fluids become thick and sticky

-        Symptoms: Build up of thick, sticky mucus -> leading to cough, lung infections, damage to respiratory tract; damage to digestive tract

Disorders Inherited as X-linked dominant rett

-        Affects ~ 1:10,000 live female births

-        Mutation in the methyl CpG binding protein 2 (MECP2) on X chromosome

-        Neurodevelopmenal disorder: Protein needed for brain development

-        Affects all body movement, loss of speech and hand use, slowed brain and head growth, seizures, and intellectual disability

Disorders Inherited as X-linked recessive

Red-Green Colour Blindness

-        No actual blindness but deficiency of colour vision

-        Cause: Fault in the development retinal cones that perceive colour

-        1:12 males, 1:200 females in populations with Northern European ancestry

Alterations in chromosome structure

-        Only very few compatible with live birth

-        Often associated with cancer

o    Deletions

o    Duplications

o    Translocations

o    Inversions

cri de chat

-        Deletion of a small portion of chromosome 5 -> affects growth and development

-        Severity of symptoms depends on size and location of the deletion

-        ~1 in 20,000 to 1 in 50,000 newborns

-        Children present with:

o    severe mental impairment

o    a small head with unusual facial features

o    cry sounds like a distressed cat

Duplications Fragile X Syndrome:

-        Affects 1:1500 males, 1:2500 females

-        X linked dominant disorder

-        Most common cause of intellectual disability

-        Affecting gene: Fragile X messenger ribonucleoprotein (FMR1) on the X chromosome

o    Expansion of the CGG trinucleotide repeat

-        Most people 29 repeats , Fragile X > 700 repeats due to duplications

o    failure in correct protein expression required for normal neural development

Translocations - Acute Myeloid Leukemia (AML)

-        Group of disorders with different translocations

-        Acute promyelocytic leukemia translocation t(15;17) -> fusing a part of the promyelocytic leukemia gene to the retinoic acid receptor α gene to encode PML-RARA

-        Affects ~ 4:100,000 Australians

-        Leukemias starting in the myeloid cell line

-        Rapid growth of poorly differentiated white blood cells -> accumulate in the bone marrow

-        Often inadequate production of red blood cells and platelets -> anaemia, easy bleeding & bruising

-        Abnormal accumulation of immature granulocytes = promyelocytes -> unable to function properly to prevent or fight infection

Inversions -        In Hemophilia A ->

mutations in the factor VIII gene -> 40% of mutations due to Inversions

Asexual reproduction

-        Offspring originates from a single organisms and inherits the parents’ genes -> identical clones -        4 types: binary fission, budding, fragmentation or parthenogenesis

Fission = binary fission:

-        Prokaryotic microorganisms and in some invertebrate, multi-celled organisms

-        After a period of growth, an organism splits into two separate organisms

Fragmentation:

-        A new organism is growing from fragments of the progenitor

-        Noticeable difference in the size of the individuals initially

Budding/Gemmation:

-        Formation of small buds on the surface of the progenitor which can develop into a new individual

Parthenogenesis:

-        An egg develops into a complete individual without being fertilized

Asexual reproduction pros and cons

Advantages:

-        Speed, no gamete formation

-        Advantage for small populations

-        Not very complex, requires less energy

-        Advantage in stable environment

Disadvantages:

-    little genetic diversity

-        Environment usually not stable long term -> want to have diversity to be able to adapt to different environments

-        overcrowding due to exponential growth

Sexual reproduction pros and cons

Advantages:

-        genetic diversity

-        Advantage in a changing environment & less susceptible to disease

Disadvantages:

-        Cost intensive – a lot of energy

-        Only 50% of the genome contribute to the offspring

-        Fewer offspring

-        Sharing of beneficial genes

Sexual or Asexual reproduction

-        Some species can reproduce sexually and asexually

-        Aphids, slime molds, sea anemones, and some species of starfish

-        When environmental factors are favorable -> asexual reproduction -> exponential population growth to take full advantage of the rich supply resource

-        When food sources depleted and or climate becomes hostile -> survival jeopardized -> sexual forms of reproduction to increase diversity

External fertilization

-        Usually occurs in aquatic environments

-        Both eggs and sperm are released into the water = spawning

-        Water protects the eggs from drying out

-        Gametes have to be released at the same time and same location

clued by

o    water temperature

o    length of daylight

o    moonlight important external stimulus

o    pheromone cues

 

Internal fertilization

-        Male deposits his sperm directly into the female's body

-        Internal fertilization of land-based animals

-        Advantage of protecting the fertilized egg from dehydration on land

-        Increases the likelihood of fertilization by a specific male = sexual selection

-        Fewer offspring produced, but their survival rate is higher

-        Often embryo isolated within the female, which limits predation on young

Oviparity

-        Fertilized eggs laid outside the female’s body and develop there

-        Embryo receives nourishment from the yolk that is a part of the egg

Viviparity

-        Fertilized eggs are retained inside the female

-        Eggs lack hard outer covering or shell

-        Embryo receives nourishment from the mother’s blood through a placenta or delivered as uterine milk

-        Offspring develops in the female and is born alive:

Ovoviviparity

-        Eggs are fertilized then retained inside the female’s body

-        Embryos do not receive direct nourishment from the mother

-        Embryo receives nourishment from the egg’s yolk

-        Young are fully developed when they are hatched

Sexual selection

-        Arises from differences in reproductive success caused by competition for access to mates

o    Male–male combat

o    Female's choice of attractive males

-        In most sexually reproducing species females select traits in males -> males compete with each other for access to females for mating

Animal mating systems

males can also compete for fertilization of a female’s eggs after mating has already occurred!

-        Competing after mating = indirect male competition = sperm competition ->results in one male being more successful than another at fertilising a female’s eggs

o    Mate guarding

o    Copulatory plug

o    Elaborate penis morphology

o    Large quantity of semen

True hermaphrodite species

-        Possess both male and female fully functional reproductive organs

-        They can produce both sperm and ova

-        Allows to potentially reproduce with any other member of their species

• Self-fertilization: Some hermaphrodites can fertilize their own ova.

• Cross-fertilization: More commonly, hermaphrodites mate with another individual, and both organisms
  exchange sperm and fertilize each other's eggs.

Species difference in reproductive tracts

• Most non-human male mammals have a penis which is stored internally until erect & a penis bone = baculum

• chickens have a Cloaca is the posterior orifice that serves as the only opening for the digestive, reproductive, and urinary tracts

• Marsupials: Female has two (or 3) vaginas - both open externally through one orifice but lead to different compartments within the uterus, Males usually have a two-pronged penis, corresponding to the females' two vaginas, Marsupials typically develop their offspring in an external pouch containing teats

Superfecundation:

-        Second conception during existing pregnancy

-        In some animals with multiple offspring, it is possible that siblings have different fathers if matings with
different fathers occurred -> genetically half siblings

Stem cells

-        Different cells in the body come from stem cells

-        Stem cells:

• Can self-renew to make more stem cells
  › sometimes after long periods of inactivity
  › mitotically divide
  › resulting cells continue to be unspecialized

• Can differentiate into a specialized cell type

• Present throughout life

Resident stem cells maintain tissue homeostasis inresponse to perturbations

How do we get different tissues

-        Different body cells contain identical DNA

-        Stem cells can specialize when stimulated = differentiate -> different genetic information is accessed -> different proteins are produced

-        Internal signals: changes in transcription or expression of genes expression regulates cell differentiation

-        External signals: chemicals secreted by other cells, physical contact with neighbouring cells, molecules in the microenvironment of the cell

Progenitor cells

● Partially differentiated
● Intermediate cell type(s) before stem cells become mature cell types
● Committed to development pathway

Replication of a progenitor cell leads to two more specialized cells: The higher the degree of differentiation, the lower the replication potential of the cell

A cell’s ability to replicate

-        Cells have limited capacity to replicate due to aging

-        Hayflick limit: After ~50 cell divisions cells become senescent

-        Telomeres are guanine-rich tandem DNA repeats on the ends of chromosomal -> provide chromosomal stability -> protect against chromosomal fusion, recombination, and terminal DNA degradation

-        End-replication problem: Telomeres shorten as a result of incomplete replication of linear chromosomes -> progressive telomere shortening -> DNA loss & damage -> programmed cell death = apoptosis

-        Enzyme telomerase can replenish and elongate chromosome telomere repeats

-        Stem cells have telomerase activity -> can replicate indefinitely

-        Level of telomerase low in the majority of human stem cells

-        Telomerase activity upregulated in rapidly replicating cells e.g. progenitor cells

The hierarchy of hematopoietic cells

-        Daily ~ 1011 new blood cells

-        Organized in a hierarchy

-        Hematopoietic stem cells -> progressively more lineage-restricted, differentiated progenitors -> produce functionally mature blood cells

-        Final cell types are terminally differentiated and do not divide

Types of stem cells

Embryonic Stem Cells:

-        Can differentiate into all cell types present in an organism

-        Immortal

Adult Stem Cells = Somatic stem cells:

-        Embryonic stem -> fetal stem cells -> with birth mature into adult stem cells

-        Reserve supply of cells that can multiply when needed (repair/regeneration)

Potency of stem cells

-        Totipotent

-        Pluripotent

-        Multipotent

-        Unipotent

-        Induced Pluripotent

 

Totipotent stem cells

-        The only totipotent/ omnipotent cells are the fertilized egg and the cells produced by the first few divisions

-        Totipotency: Ability of one isolated cell to produce a fertile, adult individual

-        Have ovum derived cytoplasmic (non-genetic) factors which are critical components of totipotency

-        Totipotent stem cells give rise to somatic stem/progenitor cells and primitive germ-line stem cells

-        Totipotent stem cells can give rise to any of the 220 cell types found in an embryo as well as extra-embryonic cells (placenta)

Embryonic stem cells

-        Cells from the inner cell mass of the blastocyst

-        Embryonic stem cells not totipotent since they cannot produce extraembryonic tissues

-        Are Pluripotent -> can give rise to differentiated cell types that are derived from all three primary germ layers of the embryo (endoderm, mesoderm, and ectoderm)

-        Lack the oocyte factors and have ~200 genes differently expressed compared to blastomeres

-        Can self-renew

Multipotent stem cells

-        Exist throughout the human body and play important roles in tissue maintenance, repair and can self-renew

-        Can develop into a limited number of cell types in a particular lineage (multi-lineage differentiation) -> develop specific types of cells (terminally differentiated cells)

-        Most adult stem cells are considered multipotent e.g. tissue stem cells and cord blood stem cells -> Haematopoietic stem cells, neural stem cells, mesenchymal stem cells etc.

Unipotent stem cells

-        Arise from multipotent cells

-        Can differentiate along only one lineage -> will only give rise to one cell type

-        Have lowest differentiation potential from all stem cells

-        Can self renew -> found in tissue that can self regenerate on a regular basis

-        e.g. muscle-stem cells, epidermal stem cells -> producing epithelial cells of skin

Adult Stem Cells - Somatic Stem Cells

-        Adult Stem Cells = Somatic Stem Cells = Progenitor cells

-        In small quantities, throughout the body -> can generate specialized cells for local area

-        Important for growth & tissue homeostasis -> replenish senescent or damaged cells

-        Maintenance and regeneration of tissues dramatically decreases with age

-        Thought to reside in a specific area of each tissue, called a “stem cell niche”

-        Can be extracted from many areas of the body including the bone marrow, fat, and peripheral blood

Induced pluripotent stem cells (iPSC)

-        Adult differentiated somatic cells that are genetically reprogrammed to a pluripotent embryonic stem cell

-        Forced to express genes important for maintaining the defining properties of embryonic stem cells

4 factors necessary for reprogramming

-        Oct3/4, Sox2, Klf4, and c-Myc

-        Human iPS cells were similar to human embryonic stem cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity

Applications of stem cells

Research

-        information about the complex events that occur during human development

-        identify how undifferentiated stem cells become differentiated

-        disease modelling

Cell Therapy

-        cell replacement therapy: traumatic spinal cord injury, Parkinson's disease, diabetes, heart disease, vision and hearing loss, burns, osteoarthritis

Drug development

-        new medications could be tested for safety on differentiated cells generated from human pluripotent cell lines, safety and efficacy

Hematopoietic stem cell transplantation

-        Bone marrow transplants: Medical procedure to replace defective bone marrow stem cells with healthy cells

-        Derived from

o    peripheral blood after stimulation of stem cell replication through growth factors

o    bone marrow removed from a large bone of the donor through a large needle

-        Replace stem cells that have been damaged by high doses of chemotherapy in patients.
A. Allogenic stem cell transplantation
B. Autologous stem cell therapy

Hematopoietic stem cell transplantation: Allogenic stem cell transplantation

-        Donor and the recipient of the stem cells are different people

-        Possibility of rejecting of tissue which is “not self”

-        Allogeneic HSC donors must have a Human Leukocyte Antigen (HLA) type that matches the recipient

-        Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications

Hematopoietic stem cell transplantation: Autologous stem cell therapy:

-        Donor –> Isolation of own stem cells –> reintroduction of own cells

-        Harvested adult stem cells purified, assessed for quality and frozen

-        Cells reintroduced in the donor/patient directly or after expansion of stem cells in the laboratory - “increasing the reserve” by transfusion

-        E.g. to replace destroyed tissue and resume the patient's normal blood cell production