Haematopoesis and immune system development

Haematopoesis

The process by which haematopoetic stem cells (HSCs) differentiate into mature blood cell types

Mature blood cell types

Arise from HSCs. Include red blood cells, granulocytes, macrophages, dendritic cells, lymphocytes, innate lymphoid cells.

Self-renewal of HSCs

HSCs can replicate themselves to maintain their population, while multipotency denotes their capability to differentiate into all types of mature blood cell.

Stem cell

A single cell that can: 1. Regenerate or self-renew 2. Differentiate (multipotent) into all diverse cell types.

Embryonic stem cells (ESCs)

Found in the inner cell mass of the early-stage embryos. ESCs are pluripotent.

Adult stem cells (Tissue specific)

Multipotent. Can only differentiate into specific tissue cells. Eg. HSCs.

Where does hamatopoiesis occur?

First occurs in the yolk sack during foetal development. Then in the dorsal aorta and produces multipotent hematopoetic progenitors. After birth hematpoesis takes place in the bone marrow.

Where do immature/ pre-HSCs undergo maturation into adult HSCs?

Fetal liver

Host HSCs are...

Quiescent during homeostatic condition (absence of infection)

LT-HSCs

Long-term HSCs. Population with a self renewal capacity.

ST-HSCs

Short-term HSCs. Lineage committed and cannot sustain their self renewal property for a long time.

What do LT-HSCs differentiate into?

ST-HSCs

What do ST-HSCs differentiate into?

Multipotent progenitors which have no detectable self renewal ability, which further divides into common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs)

Haematopoetic stem cell niche

Specialised microenvironment in the bone marrow where hematopoetic stem cells (HSCs) live.

Niches HSCs reside in

An osteoblastic niche (near bone forming cells) and a vascular niche in the bone marrow (Near blood vessels).

What does the HSC niche control

Differentiation (forming blood cells like RBCs, WBCs, platelets), and quiescence (keeping HSCs inactive when not needed). Survival and protection from damage.

Quiescence in HSCs

In the G0 phase. Reversible, non-dividing state/ Prevents exhaustion, as excessive replication can lead to impaired capacity for self renewal. Protects HSCs from the accumulation of replication-associated DNA damage.

Active HSCs

HSCs that have undergone or are undergoing cell division

Cycling HSCs

Are in G1-S-G2-M phases of the cell cycle.

Where do most HSCs reside in the cell cycle during homeostasis?

G0

Dormant HSCs

Distinct subpopulation of the quiescent HSCs which are characterised by a deeper state of quiescence.

Regulation of haematopoesis by transcription factors

Transcription factors regulate HSCs activities: quiescence, self-renewal, multipotency, and differentiation to the several lineages.

Cytokines

Small signalling proteins, produced by many different immune cells that act as chemical messengers, allowing cells to communicate and coordinate responses.

Different types of Cytokines

Interleukins (IL), interferons, TNFs, Colony-Stimulating factors (CSF), Chemokines for migration of immune cells.

Growth factors

Regulate cell proliferation, differentiation, and tissue repair

Examples of growth factors

TPO, EPO

Thrombopoietin (TPO)

Growth factor that regulates platelet production

Where is TPO produced?

Predominantly the liver. Also the kidney, spleen, and stromal cells in the bone marrow

What is TPO production regulated by?

Platelet numbers

How does TPO exert its effect?

Through the activation of its receptor (MPL) on platelets

Erythropoietin (EPO)

Regulates red blood cell production

Where does EPO act?

Committed erythroid progenitors.

Normoblasts (Erythroblasts)

Basophilic erythroblast, polychromatic erythroblasts, orthochromatic erythroblasts

BFU-E

Burst forming unit Erythroid. The earliest committed erythroid progenitor.

How do transcription factors bind Erythroid differentiation?

by turning on red-cell-specific gene and turning of stem cell and alternative lineage programs, thereby committing cells to become functional blood cells.

CFU-E

Colony forming unit Erythroid. Matures through several erythroblast stages, synthesising haemoglobin and undergoing cellular transformations in preparation for enucleation.

Erythroblast stages CFU-E matures through

proerythroblast, basophilic, polychromatic, and orthochromatic

Orthochromatic erythroblast

expels its nucleus to form a reticulocyte which enters the bloodstream and matures into a functional erythrocyte within one week. The resultant biconcave is primed for efficient oxygen transport.

What happens at the proerythroblast stage?

GATA-1 binds FOG-1 and together with rising EKFL levels, activates erythroid specific genes necessary for differentiation.

How do prokaryotes protect themselves?

By using restriction enzymes and clustered regularly interspaced palindromic repeats (CRISPRs) being able to degrade invading foreign pathogens.

What does adaptive immunity appear in?

Jawed vertebrates.

TGF-Beta

Regulates both innate and active immunity. Evolutionarily preserved cytokine.

MIF

macrophage inhibitory factor. Conserved proinflammatory cytokine present from jawed fish to mammals,

AIF-1

Allograft inflammatory factor-1. Cytokine described in vertebrates and invertebrates.