Lecture 13: tissue regeneration + adult stem cells Flashcards
what programmes of regeneration are out there?
1.Morphallaxis in hydra:
the repurposing of cells or tissues left after an injury, without these cells dividing.
= complete and functional, but smaller animal.
occurs in animals with low cell numbers, few distinct cell types and simple body plans
- Epimorphosis:
regeneration of tissues and organs from differentiated cells which de-differentiate, so back-track to a precursor cell state, where they can divide again. Once cell numbers have been made up, the cells differentiate and tissues are being patterned, and shape and function is being restored.
various organs can regenerate via epimorphosis. Yet also mammalian cells can be brought to de-differentiate and re-enter cell cycle by suppressing pathways used in cell cycle control and cancer protection
A distinctive feature of newt regeneration is the prominence of injury-evoked reversal of the terminally differentiated state of cells. This means the formation of a blastema
- Compensatory regeneration - humans
when differentiated cells re-enter cell cycle to make up for the lost cell numbers without giving up their differentiated state.
= cells still carry out the required function in the affected organ
in mammalian liver:
partial hepatectomy, i.e. the surgical removal of parts of the liver,
the remaining lobes enlarge to compensate.
+ all 5 types of liver cells
start to divide again to compensate for the loss
Each cell type retains cellular identity + stays fully functional, they keep playing their assigned roles.
Tissue loss is sensed through the blood stream. This leads to the production of HGF/SF (hepatocyte growth factor/ scatter factor) which stimulates cell proliferation
Each cell type (hepatocytes, duct cells, fat-storing (Ito) cells, endothelial cells, Kupffer macrophages)retains cellular identity
Cells retain the ability to make liver specific enzymes for glucose regulation, toxin degradation, bile production, albumin (and other plasma proteins) production etc
Tissue loss is sensed through the blood stream. This leads to the production of HGF/SF (hepatocyte growth factor/ scatter factor) which stimulates cell proliferation
- Stem cell mediated regeneration:
Stem cells are a special types of undifferentiated precursor cells, and a number human tissues are set up with stem cells. Stem cells may be quiescent, only to be activated when an organ was damaged, for example skeletal muscle stem cells. Stem cells may be active all
the time, such as haematopoietic stem cells in the bone marrow that replenish the blood.
stem cells
undifferentiated precursor cells that produce a self-renewed stel cell and a differentiating cell via asymmetric cell division.
Blastema formation
First, the wound is sealed by an wound epidermis
the epidermis forms an apical ectodermal cap
cells from all cut tissues including the bone and the skeletal muscle lose their normal appearance, de-differentiate and form a blastema, which is a conglomerate of undifferentiated, proliferating cells
Shh in the caudal blastema acts in a feedback loop with anteriorly expressed of FGF8, with sustained FGF signalling required for persistent blastema cell proliferation.
RA is synthesized by the wound epidermis
It forms a proximodistal and anteroposterior gradient
Hox (and other) genes are expressed in response to this gradient, thereby establishing positional information
prolonged RA exposure tells blastemal cells that they are proximal.
connective tissue type cells which are the major contributor to the blastema during limb regeneration and give rise to cartilage, bone, tendons, peri-skeleton and dermal and interstitial fibroblasts
which state cells go back to when dedifferentiating
GFP expressing cells did not contribute to muscle, indicating that the cells did not back-track to a stage where they could have formed either muscle or bone. Instead , the only went back to a connective/cartilage/bone competent precursor cell.
how cells may be able to dedifferentiate and re-entre cell cycle
during development, differentiating cells establish the gene expression patterns needed for the job and withdraw from cell cycle
Differentiated cells in a tissue can be turned into induced pluripotent stem cells (iPS cells) that, in the mouse, can contribute to a developing embryo and its germ line. Depending on the method of gene activation/gene transfer, these cells may have an increased rate of tumour formation
how cells may be able to dedifferentiate and re-entre cell cycle
during development, differentiating cells establish the gene expression patterns needed for the job and withdraw from cell cycle
how mitotically active cells enter cell cycle.
G1, cyclins activate cyclin dependent kinases to phosphorylate the retinoblastoma protein, pRb. This leads to the release of the E2F transcription factors which in turn activate genes needed for cell cycle progression
in a cell not meant to divide, cyclin dependent kinase inhibitors or Cdkns inhibit the Cdks
preventing phosphorylation of the retinoblastoma protein
how in a muscle precursor cell, Cyclin-Cdk complexes promote proliferation and suppress differentiation
In muscle the transcription factor MyoD controls the entry of a muscle precursor cell into differentiation, culminating in the expression genes encoding contractile proteins. But when a precursor cells is still actively dividing, Cdk2 phosphorylates MyoD, thereby inactivating it.
in a differentiating cell, through the build-up of MyoD, Cdkn levels rise.
aided by the ARF-p53 axis. As a result, Cyclin-Cdk complexes are blocked, the RB protein and MyoD are not phosphorylated, cell cycle is inhibited and differentiation promoted
embryonic stem cells
a totipotent cell, the zygote, which can and will give rise to any embryonic tissue, any extraembryonic tissue, and the germ cells.
Cell division will give rise to a morula, and then a blastula stage embryo
an outer layer of cells forms the trophoblast that will provide the embryo derived portion of the placenta.
inner cell mass
the cells that will form the body of the developing organism and the germ cells. These cells cannot make trophoblast any more = pluripotent
where Tissue culture cells derived from
not all stem cells are pluripotent
haematopoietic stem cells – make all sorts of blood cells but not an entire embryo plus germ cells
another, tissue-specific stem cell, the adult muscle stem cell also known as satellite cell.
- when muscle is damaged, the satellite cell does become activated and starts dividing. Eventually cells that activate MyoD and differentiate into muscle are produced. These cells replace the damaged muscle fibres. Notably, also cells are being produced that return to quiescence and become a Pax7 expressing satellite cell once more
an ordinary precursor cell which would eventually be consumed by differentiation.
The precursor cell undertakes asymmetric cell divisions, in one go generating a copy of itself and a cell destined for differentiation
where, either in muscle regeneration or in fact in embryonic muscle development, a muscle stem cell comes from
the paraxial or somitic mesoderm expressing Tbx6 a
