lecture 2 - haemopoietic stem cells Flashcards
What is the definition of haematopoiesis, where does it primarily occur and how many HSCs are found in adult humans?
Haematopoiesis is the production of haematopoietic (blood) cells - all of the blood cells in the body
All blood cells in the body are descended from a rare population of stem cells (HSCs), which are able to self-renew and give rise to differentiated cells of all haematopoietic lineages.
It predominantly occurs in red bone marrow (medullary)
50,000-200,000 active HSCs are found in humans
Why are HSCs the best characterised and utilised stem cells (6 reasons)?
Tissue accessibility and ease of sampling - relatively non-invasive to isolate bone marrow, or can be taken from peripheral blood
Tissue properties - soft with high cellularity, easy to fragment and study
Ease of identification - mature cells and their immediate precursors are morphologically distinct
robust and reliable reconstitution assays
straightforward delivery of test cells - direct injection into BM
availability of congenic/mutant/engineered mouse strains - facilitates tracking of the fate and developmental potential of the transplanted cells
What is the stem cell niche?
In a tissue, cells have neighbouring cells that they contact via a variety of cell surface receptors
the combination of signalling contributes to gene expression and therefore cell fates
cells exist in different states in the body (niche) - e.g. neighbouring cell might be different - all of these influence the cell
Describe the location of the HSC niche
The HSC niche is the bone marrow - many studies have been performed using mice, which have significant differences in their haematopoiesis than that of humans
Studies looking at location of HSCs have found that they are much closer to sinusoids than to TZ vessels and to arterioles.
non-dividing HSCs enriched in central marrow, dividing HSCs are enriched in the endosteal region.
Describe signalling in the HSC niche - what intrinsic and extrinsic factors affect the niche
HSC fate is regulated by both cell intrinsic and cell extrinsic factors
extrinsic - ROS, hypoxia (affecting cell cycle entry)
intrinsic - TFs, cell cycle regulators (affecting cell cycle entry), TFs and cell cycle regulators (affecting quiescence entry)
Leptin receptor positive perivascular stromal cells (Lepr+) help secrete cytokines that maintain HSCs
CXCL12 and SCF are particularly important in HSCs
quiescence is maintained by CXCL12 - helps maintain them in a haemopoietic state
Describe emerging evidence for HSC niche
mice were genetically engineered to label a subset of quiescent LT-HSCs
most LT-HSCs were located near sinusoids
hypoxic niche has long been associated with maintaining quiescence
LT-HSCs have low motility under SS conditions - LT-HSC became more motile and their numbers increased when stimulated with cyclophosphamide/GCSF
Describe HSC ageing - niche changes, genetic changes (CHIP)
ageing results in repair mechanisms of DNA being reduced - accumulate over time
In HSCs, some action of these changes is an accumulation of common myeloid precursor
increased propensity for malignancy in these myeloid populations
CXCL12 and SCF promote retention and maintenance
CHIP (clonal haematopoiesis of indeterminate potential) may occur - this is where you get specific cells clonal expanding within the pool of HSCs
greatest contribution from mutations in genes involved in epigenetic regulation \
many of the common mutations found in CHIP are drives of AML and other blood cancers
What are the applications of HSCs (hint: transplantation)?
HSC can be used in bone marrow transplantation and is currently the only established stem cell therapy
Graft verses host disease can occur (GvHD) - possible complication
can be reduced by enrichment of CD34+ HSCs (magnetic cell sorting)
remove cells that can contribute to GvHD - drastically improves the severity and likelihood of GvHD occurring
there are also other therapeutic uses, such as being used to treat HIV
