4 Structure of the Marrow and the Hematopoietic Microenvironment Flashcards
The most primitive pool consists of pluripotential lymphohematopoietic stem cells with the capacity for continuous self-renewal
Hematopoietic stem cells (HSCs)
The earliest hematopoietic cells develop in the __________________ during late gastrulation and form the primitive hematopoietic system.
Blood islands of the extraembryonic yolk sac
Most primitive blood cells produced are
Erythrocytes
The predominant cell produced by definitive hematopoiesis during prenatal development
Erythrocytes
Smaller than the primitive erythrocytes, and their hemoglobin contains the fetal and adult hemoglobins
Important for the development of endothelial cells that form blood vessels and HSCs located within these vessel
Increases proliferation and self-renewal of HSCs by upregulating SCF/KIT ligand in HSCs, but not in adjacent endothelial cells
BMP-4
The differentiation of HSCs from hemangioblasts and/or hemogenic endothelium requires the signaling protein _______and the transcription factors _______________
Notch1
GATA-2, MYB, and Runx1
Release of HSCs from the murine fetal liver coincides with the progressive loss of 2 adhesion proteins, ____________ and ______________
CD144 (VE-cadherin)
CD41 (integrin α2b)
Migration of circulating HSCs to their supporting marrow niches, which are formed by cells expressing aminopeptidase A but not endoglin or Thy1, is directed by the synergistic action of ____________and ____________
C-X-C chemokine CXCL12/ stromal cell-derived factor 1 (CXCL12)
Cytokine stem cell factor (SCF)
Receptors for:
C-X-C chemokine CXCL12/ stromal cell-derived factor 1 (CXCL12) :
Cytokine stem cell factor (SCF):
C-X-C chemokine CXCL12/ stromal cell-derived factor 1 (CXCL12) : CXCR4
Cytokine stem cell factor (SCF): KIT
In the human, marrow hematopoiesis begins at the ________week of gestation in specialized mesodermal structures termed ______________
11th week of gestation
Primary logettes
By the _________ year of life, a significant number of fat cells have appeared in the diaphysis of the human long bones
Fourth year
These cells slowly replace hematopoietic elements and expand centripetally until, at approximately age 18 years,: hematopoietic marrow is found only in the :
Vertebrae, ribs, skull, pelvis, and proximal epiphyses of the femora and humeri
The principal blood supply of the marrow
Nutrient artery
In the marrow cavity, the nutrient artery bifurcates into ascending and descending central or medullary arteries from which radial branches travel to the inner face of the cortex.
The sinuses collect into a large central sinus from which the blood enters the systemic venous circulation through
Emissary veins
The most hypoxic vessels and interstitium
Sinusoids
The cellular components of marrow niches
(a) endothelial cells,
(b) MSCs and their descendants that form chondrocytes, osteoblasts, osteocytes, fibroblasts, and adipocytes
(c) terminally differentiated progeny of HSCs such as megakaryocytes, macrophages, and lymphocytes
Major source of CXCL12 and SCF for the common lymphoid and myeloid progenitor cells
CXCL12–abundant reticular (CAR) cells
They form a major barrier and control chemicals and particles entering and leaving the hematopoietic spaces, with overlapping or interdigitating unions permitting volume expansion
Endothelial Cells
Synthesize argentophilic fibers that, with their cytoplasmic processes, extend into the hematopoietic compartments forming a meshwork on which hematopoietic cells rest
Adventitial Reticular Cells
Transcription factors promoting adipocyte differentiation
Marrow adipocytes create a negative hematopoietic microenvironment that reduces development of HSCs and early-stage common hematopoietic progenitors.
However, during marrow regeneration, adipose tissue appears to mediate hematopoietic recovery by secretion of SCF
Peroxisome proliferator-activated receptor γ2 (PPARγ2)143 and CCAAT enhancer binding protein (C/EBP)
3 major functions of Osteoblasts:
- Formation of new bone by regulating the secretion of the bone matrix proteins
- Regulation of bone resorption via osteoclast activity
- Regulation of the hematopoietic environment mainly by their secretion of cytokines
Controls differentiation of MSCs into osteoblasts or adipocytes
Ebf3
Runx2: osteoblasts
PPARγ: adipocytes
Are multinucleated giant cells derived from fusion of progenitor cells of the monocyte/macrophage lineage of the HSC
Osteoclasts
Resorb and remodel bone, regulate osteoblast activity, and help control the HSC entry into and exit from the marrow
Osteoclasts
When murine osteoclast activity and/or number are reduced or eliminated through null mutations, marrow cavities fail to form, resulting in
Osteopetrosis
A major regulatory mechanism by which osteoblasts and osteoclasts interact is the
RANK/ RANKL/osteoprotegerin (OPG) system of signaling
A decoy receptor for RANKL that binds and inactivates RANKL, thereby preventing its binding to RANK
OPG
Thus, osteoclastic activity is decreased when OPG concentrations are high and increased when they are low
It is where early lymphoid progenitors (ELPs) undergo differentiation into T cells
Thymus
The marrow acts a secondary organ for the proliferation of mature CD8+ and CD4+ memory T lymphocytes.
Approximately_______% of developing marrow B cells are lost at the immature stages from autoantigen recognition.
85%
How do marrow macrophages differ from osteoclasts
- Single nucleus
- Expression of F4/80 antigen
- Absence of TRAP and calcitonin receptors
Specialized macrophages that form a canopy over the active osteoblasts and osteoclasts on the endosteal surface, thereby coordinating the activities of osteoblasts and osteoclasts
Incharge of phagocytosis of apoptotic cells and cellular debris that accompany bone remodeling
Osteomacs
Macrophages that act to retain in the marrow those HSCs and early progenitor cells that are capable of circulation in the blood and comprise the central macrophages of erythroblastic islands that interact directly with erythroid cells,enhancing their proliferation and differentiation
CD169 (sialoadhesin/siglec-1)-expressing macrophages
The main cell-surface GAG in long-term marrow cultures
Heparan sulfate
The major secreted species of proteoglycans
Chondroitin sulfate
Stimulate artificial sulfated GAG synthesis, increase chondroitin sulfate synthesis and hematopoietic cell production
D-xylosides
Heparin-containing and heparan sulfate-containing proteoglycans interact with laminin and __________ collagen
type IV collagen
Collagen types associated with:
Microvascular walls:
Basal lamina beneath endothelial cells:
Microvascular walls: Collagen types I and III
Basal lamina beneath endothelial cells: Collagen type IV
Collagen that binds von Willebrand factor and is a strong cytoadhesive component of the marrow microenvironment
Collagen VI
Fibril-associated collagen that promotes hematopoietic cell adhesion of myeloid and lymphoid cell lines
Collagen type XIV
Multidomain glycoproteins with mitogenic and adhesive sites, are major components of the extracellular matrix and basement membranes
Laminin
A multifunctional extracellular matrix protein initially identified in platelet α granules, has domains that interact with collagen and fibronectin and may participate in stem cell lodgement
Thrombospondin
A major cytoadhesive glycoprotein
Vitronectin
A glycoprotein produced by osteoblasts and hematopoietic cells in the marrow, binds to fibronectin and collagen.
Osteopontin
The earliest progenitor cells committed solely to erythroid differentiation, are not erythropoietin (EPO)-dependent
BFU-Es
Unlike, CFU-Es and their immediate progeny, proerythroblasts, depend upon EPO to prevent apoptosis.
The major regulator of erythropoiesis, tightly controls production rates and is produced by the kidneys in response to hypoxia, which, in turn, is regulated by numbers of circulating red blood cells, as sensed by tissue oxygen delivery
EPO
Erythroid differentiation occurs within _______________, which consist of a central stromal macrophage surrounded by adherent erythroid cells in all differentiation stages of proerythroblast through orthochromatic erythroblast.
Erythroblastic islands (EBIs)
The major regulator of megakaryocyte development
TPO
TPO, which is required by HSC and the megakaryocytic lineage cells, is primarily produced by the
Liver
Transcription factors for:
Erythroid/megakaryocytic progenitor differentiation:
B-cell differentiation:
Granulocytic differentiation:
Monocytic differentiation:
Erythroid/megakaryocytic progenitor differentiation: GATA-1
B-cell differentiation : Pax5
Granulocytic differentiation: C/EBPα
Monocytic differentiation: PU.1
Two hematopoietic growth factors have specific lineage targets for late-stage granulocytic cells
Eosinophil progenitors:
Neutrophilic progenitors:
Eosinophil progenitors: IL-5
Neutrophilic progenitors: G-CSF
