Ch2 Hematopoiesis

Cells in the blood

erythrocytes, leukocytes, platelets

Perinatal hematopoiesis

• mainly yolk sac in the beginning, then in declines and the liver picks up, following a decline in liver with an increase in bone marrow

Bone marrow microenvironment

• stem cells

• stromal elements

Stem cells in the bone marrow

• hematopoietic stem cells

• hematopoietic progenitor cells

• mesenchymal cells

Stromal elements in the bone marrow

• endothelial cells

• stromal cells

• macrophages

• adipocytes

• extracellular matrix (ECM)

What are some hematopoietic precursors?

• myeloid

• lymphoid

• megakarocytic

Bone marrow cell origins

• Hematopoietic stem cells (HSC)

• Hematopoietic progenitor cells (HPC)

• Hematopoietic precursor cells

• Mature hematopoietic cells

What is the starting cell for all blood cells?

HSC

What are HPC?

the precursor cells before you get to the specilizations (RBC vs. WBC vs. platelet)

Mature hematopoietic cells

basophils, eosinophils, neutrophils, red blood cells, etc.

Mesenchymal stem cells are

• multipotent

what is multipotent?

can form all cell types within a certain lineage

Cells produced by mesenchymal cells

• stromal cells

• adipocytes

• endothelial cells

• fibroblasts

• osteoblasts

• chondroblasts

Stromal cells

supporting framework

Adipocytes

stores fat, supports hematopoiesis

Endothelial cells

forms blood vessels

Fibroblasts

produce collagen

Osteoblasts

produce bone

Chondroblasts

produce cartilage

Hematopoietic cells are the ______ differentiated type of hematopoietic cells

least

HSC have what kind of replication?

sustained self replication

• replicates very slowly, one every 8-10 weeks

Multipotent

can differentiate into all blood cell types and some tissue cell types

• macrophages, dendritic cells, osteoclasts, mast cells

HSC as ______ of nucleated marrow cellularit?

less than 0.0001%

Going down the line, the hematopoietic progenitor cells have a heightened or lowered ability for self replication?

lowered

HPC have _____ self-replication

• limited

HPC require replenishment by?

HSC’s

HPC replicate more rapidly than

HSC

Does HPC or HSC have a more restricted lineage?

HSC

HPC are higher in adults or neonates?

neonates

Common lymphoid progenitor (CLP)

• T/NKP

• BLP

T/NKP

T lymphocyte-natural killer cell progenitor

BLP

B lymphocyte progenitor

Common myeloid progenitor (CMP)

• MkEP

• GMP

MkEP

• megakaryocyte-erythroid progenitor (RBC and platelets)

GMP

granulocyte-monocyte progenitor

• neutrophil, eosinophil, monocyte, basophil, dendritic cell, mast cell

Autocrine

responds to its own signal

Paracrine action

• cell releases signal to influence nearby cell

Endocrine signaling

from far away/circulation

Basal growth factor signaling =

steady state

Growth factor signaling increased results in

• increase in cell production

• decrease in apoptosis

Growth factor signaling decreased results in

• decrease cell production

• increase apoptosis

Glycoproteins

promote. hematopoietic cell proliferation, maturation, survival

Where are glycoproteins produced?

in marrow (paracrine and autocrine)

also in peripheral tissues (endocrine)

Hematopoietuc Growth Factors: Nomenclature, cytokines such as:

• colony stimulating factors (CSF)

• interlukins

• poietins

Interleukins

inflammation and immunity

Hematopoietic cells must have an appropriate surface receptor to respond to?

to a specific grwoth factor

What signals the bone marrow to produce new RBC?

EPO (erthropoietin)

EPO

• glycoprotein growth factor

• proliferation, differentiation, and survival of mature stem and progenitor cells

Main mechanism of EPO

inhibits apoptosis

An increase in Epo decreases what?

marrow transit time and promote early release of stress reticulocytes (large forms)

Main production site of EPO?

Kidney

Sites of EPO synthesis

renal interstitial cells (endocrine action and signaling

When is EPO produced?

in response to decreased renal oxygenation

Minor/Extrarenal production sites of EPO?

• liver (especially in the mammalian fetus

• bone marrow macrophages and erythroid cells

One rubriblast produces

16-32 mature RBC

Blood loss anemia results in a

decrease in O2

• causing tissue hypoxia

Tissue hypoxia results in an increase in

EPO

Regenerative anemia

increase production of RBC

What can inhibit erythropoiesis?

insufficient/lack of EPO

Lack of EPO results in

increase precursor apoptosis

Inflammatory cytokines at high concentrations decrease

EPO

• ex: IL-1 and tumor necrosis factor (TNF-a)

• contributes to anemia of inflammatory disease

Inhibitors of EPO may induce _______ directly

apoptosis

Nutrients required for erthropoiesis

• amino acids/ essiential fatty acids

• Metallic Irons

• Vitamins

Metallic ions for erythropoiesis

• iron

• copper

• cobalt

Iron

essential component of heme

• deficiency common

Copper

critical for iron absorption/metabolism

• deficiency rare

Cobalt

required for synthesis of cobalamin (ruminants)

• deficiency rare

B6 (Pyridoxine)

cofactor in heme synthesis

• deficiency rare

B9 (folate)

• required for normal erythrocyte maturation

B12 (Cobalamin)

involved in folate metabolism

• deficiency uncommon

Erythroid cells develop around?

macrophages

• erythroid/erythroblastic islands

How do macrophages influence the microenvironment?

• source of early/intermediate acting growth factors (SCF, IL-3, GM-CSF)

• Erythropoietin

• provide nutrients

• phagocytose expelled nuclei and damaged erthrocytes

• iron recylcled

Erythropoietin

endocrine action and signaling

What inhibits macrophages providing nutrients to the micronenvironment?

inflammatory cytokines

Marrow transit time

about a week

Growth factors for granulocytes and monocytes?

Granulocyte colony stimulating factor (G-CSF)

Granulocyte/Monocyte colony stimulating factor (GM-CSF)

What are G-CSF and GM-CSF produced by?

• fibroblasts and endothelial cells

• T-lymphocytes and mononuclear phagocytes (macrophages)

What are G-CSF and GM-CSF produced in response to?

inflammatory cytokines

G-CSF and GM-CSF increase in production of what?

myeloid progenitors and precursors and decrease transit time

G-CSF and GM-CSF are both important for

granulocyte development

GM-CSF is important for

monocyte development

Mature neutrophils in marrow can release what?

inhibitory substances to inhibit Granulopoiesis

• neutrophils clear circulating G-CSF by binding to receptors (negative feedback)

granulopoiesis

process of producing granulocytes

Mature neutrophils in perpheral tissues remove stimulus for

granulopoiesis

Eosinophils

• marrow storage pools like neutrophils

• IL-3 and GM-CSF for early progenitors

• IL-5 from Th2 lymphocytes for terminal maturation

IL5 only effects

eosinophils

Basophils

• produced from a bi-potential basophil/mast cell progenitor

• growth factors similar to those for eosinophils

Mast cells

• MaP released from marrow to blood (not recognizable)

• terminal differentiation in tissues

• stem cell factor important for formation (though other cytokins may be involved)

Basophils and Monocytes have

no defined growth factor

Monocytopoiesis

• IL-3, GM-CSF, M-CSF, and IL-34

Monocytopoiesis has a _________ time

short generation

Monocytopoiesis becomes what?

macrophages or dendritic cells in tissues

• influenced by amounts of various cytokines

Lymphocytes

• arise from common lymphoid progenitor (CLP)

  • B and T lymph

B-lymph

• in Bursa of Fabricius (birds)

• in Bone marrow (mammals)

  • maturation

T-lymph

mature in thymus

NK cells

develop in multiple tissue sites

Thrombopoiesis

• endomitosis

  • typically 2-5 nuclear reduplications without division

  • megakaryocyte

Megakaryocyte niche

located outside the vascular sinuses

• platelets shear off into vasculature due to blood circulation (proplatelet processes extend into vascular sinuses)

Only mammals have

megakaryocytes

Non-mammals have what kind of thrombocytes?

nucleated

• undergo typical mitosis