The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing.
Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin(-)c-Kit(+)Sca-1(+)) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34(+)VEGFR(+)) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4-CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1α in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BM-PCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1α and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferation.
Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. paolo.fiorina@childrens.harvard.edu
Paolo
P
Fiorina
Giorgio
G
Pietramaggiori
Saja S
SS
Scherer
Mollie
M
Jurewicz
Jasmine C
JC
Mathews
Andrea
A
Vergani
Gebhard
G
Thomas
Elena
E
Orsenigo
Carlo
C
Staudacher
Stefano
S
La Rosa
Carlo
C
Capella
Adelaide
A
Carothers
Hans-Gunter
HG
Zerwes
Livio
L
Luzi
Reza
R
Abdi
Dennis P
DP
Orgill
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000150:complications / Q000628:therapy
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor