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Diabetes impairs stem cell and proangiogenic cell mobilization in humans
Gian Paolo Fadini1, Mattia Albiero, Saula Vigili de Kreutzenberg
1Department of Medicine, University of Padova, Padova, Italy. gianpaolofadini@hotmail.com
Insights
Diabetes impairs the mobilization of crucial stem and proangiogenic cells, hindering tissue repair and increasing cardiovascular risk. This is linked to abnormal CD26/DPP-4 regulation in patients with diabetes mellitus.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Endocrinology
Background:
- Diabetes mellitus (DM) is a known risk factor for cardiovascular disease, partly due to reduced vascular regenerative capacity.
- Bone marrow (BM) alterations in DM are observed in experimental models, but human BM function in DM remains understudied.
- Vascular regenerative cells, crucial for tissue repair, are often derived from the bone marrow.
Purpose of the Study:
- To investigate the mobilization of stem and proangiogenic cells in individuals with and without diabetes mellitus.
- To compare the bone marrow's responsiveness to granulocyte colony-stimulating factor (G-CSF) in diabetic and non-diabetic subjects.
- To assess the in vivo angiogenic potential of peripheral blood cells in both groups.
Main Methods:
- A prospective trial (NCT01102699) involving 24 individuals with DM and 14 controls.
- Administration of human recombinant granulocyte colony-stimulating factor (hrG-CSF) to stimulate bone marrow cell mobilization.
- Quantification of circulating stem/progenitor cells (e.g., CD34+, CD133+) and white blood cell counts before and after hrG-CSF.
- Evaluation of peripheral blood mononuclear cell proangiogenic capacity using the Matrigel plug assay.
Main Results:
- Individuals without DM showed significant mobilization of CD34+ and other progenitor cells post-hrG-CSF.
- Patients with DM exhibited impaired mobilization of hematopoietic stem cells (CD34+, CD133+) and endothelial progenitors (CD133+KDR+).
- The in vivo angiogenic capacity increased in controls but not in patients with DM after hrG-CSF; DM was associated with impaired CD26/DPP-4 upregulation on CD34+ cells.
Conclusions:
- Stem and proangiogenic cell mobilization in response to hrG-CSF is significantly impaired in individuals with diabetes mellitus.
- This impairment may be attributed to dysregulated CD26/DPP-4 expression on stem cells in DM.
- These cellular deficits likely contribute to compromised tissue repair and increased cardiovascular complications in diabetes.
Objective:
Diabetes mellitus (DM) increases cardiovascular risk, at least in part, through shortage of vascular regenerative cells derived from the bone marrow (BM). In experimental models, DM causes morphological and functional BM alterations, but information on BM function in human DM is missing. Herein, we sought to assay mobilization of stem and proangiogenic cells in subjects with and without DM.
Research Design And Methods:
In a prospective trial (NCT01102699), we tested BM responsiveness to 5 μg/kg human recombinant granulocyte colony-stimulating factor (hrG-CSF) in 24 individuals with DM (10 type 1 and 14 type 2) and 14 individuals without DM. Before and 24 h after hrG-CSF, we quantified circulating stem/progenitor cells and total and differential white blood cell counts. We also evaluated in vivo the proangiogenic capacity of peripheral blood mononuclear cells using the Matrigel plug assay.
Results:
In response to hrG-CSF, levels of CD34(+) cells and other progenitor cell phenotypes increased in subjects without DM. Patients with DM had significantly impaired mobilization of CD34(+), CD133(+), and CD34(+)CD133(+) hematopoietic stem cells and CD133(+)KDR(+) endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of peripheral blood mononuclear cells significantly increased after hrG-CSF in control subjects without DM, but not in patients with DM. DM was also associated with the inability to upregulate CD26/DPP-4 on CD34(+) cells, which is required for the mobilizing effect of granulocyte colony-stimulating factor.
Conclusions:
Stem and proangiogenic cell mobilization in response to hrG-CSF is impaired in DM, possibly because of maladaptive CD26/DPP-4 regulation. These alterations may hamper tissue repair and favor the development of cardiovascular complications.
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