Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1.
Complement has recently been implicated in developmental pathways and noninflammatory processes. The expression of various complement components and receptors has been shown in a wide range of circulating myeloid and lymphoid cells, but their role in normal hematopoiesis and stem cell homing has not yet been investigated. We report that normal human CD34(+) cells and lineage-differentiated hematopoietic progenitors express the complement anaphylatoxin C3a receptor (C3aR) and respond to C3a. Moreover, C3a, but not the biologically inactive desArg-C3a, induces calcium flux in these cells. Furthermore, we found that C3 is secreted by bone marrow stroma and that, although C3a does not influence directly the proliferation/survival of hematopoietic progenitors, it (1) potentiates the stromal cell-derived factor 1 (SDF-1)-dependent chemotaxis of human CD34(+) cells and lineage-committed myeloid, erythroid, and megakaryocytic progenitors; (2) primes SDF-1-dependent trans-Matrigel migration; and (3) stimulates matrix metalloproteinase-9 secretion and very late antigen 4 (VLA-4)-mediated adhesion to vascular cell adhesion molecule 1 (VCAM-1). Furthermore, we found that murine Sca-1(+) cells primed by C3a engrafted faster in lethally irradiated animals. These results indicate that normal human hematopoietic stem and progenitor cells express functional C3aR and that the C3aR-C3a axis sensitizes the responses of these cells to SDF-1 and thus may be involved in promoting their homing into the bone marrow via cross talk with the SDF-CXC chemokine receptor-4 (CXCR4) signaling axis. C3a is the first positive regulator of this axis to be identified.
Reca
Ryan
R
Stem Cell Biology Program, University of Louisville, Louisville, KY 40202, USA.
Mastellos
Dimitrios
D
Majka
Marcin
M
Marquez
Leah
L
Ratajczak
Janina
J
Franchini
Silvia
S
Glodek
Aleksandra
A
Honczarenko
Marek
M
Spruce
Lynn A
LA
Janowska-Wieczorek
Anna
A
Lambris
John D
JD
Ratajczak
Mariusz Z
MZ
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D015926:Complement C3a / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016177:Macrophage-1 Antigen / Q000235:genetics*; D008565:Membrane Proteins; D011951:Receptors, Complement / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D015703:Antigens, CD; D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D011951:Receptors, Complement; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; C085567:complement C3a receptor; D015926:Complement C3a