RESUMEN
Objective- To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results- Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2 (extracellular signal-regulated kinases 1/2). TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK (phospho Thr202/Tyr204 ERK1/2) and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis. Conclusions- TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis.
Asunto(s)
Movimiento Celular , Glicoproteínas de Membrana/metabolismo , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , Pericitos/metabolismo , Vena Safena/metabolismo , Animales , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Miembro Posterior , Humanos , Isquemia/genética , Isquemia/metabolismo , Isquemia/fisiopatología , Isquemia/cirugía , Masculino , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Ratones Desnudos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Pericitos/trasplante , Fosforilación , Receptores CXCR/genética , Receptores CXCR/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
RATIONALE: Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities. OBJECTIVE: Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements. METHODS AND RESULTS: SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively. Single or dual cell therapy (300 000 cells of each type per heart) was tested in infarcted SCID (severe combined immunodeficiency)-Beige mice. SVPs and CSCs alone improved cardiac contractility as assessed by echocardiography at 14 days post myocardial infarction. The effect was maintained, although attenuated at 42 days. At histological level, SVPs and CSCs similarly inhibited infarct size and interstitial fibrosis, SVPs were superior in inducing angiogenesis and CSCs in promoting cardiomyocyte proliferation and recruitment of endogenous stem cells. The combination of cells additively reduced the infarct size and promoted vascular proliferation and arteriogenesis, but did not surpass single therapies with regard to contractility indexes. SVPs and CSCs secrete similar amounts of hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, stem cell factor, and stromal cell-derived factor-1, whereas SVPs release higher quantities of angiopoietins and microRNA-132. Coculture of the 2 cell populations results in competitive as well as enhancing paracrine activities. In particular, the release of stromal cell-derived factor-1 was synergistically augmented along with downregulation of stromal cell-derived factor-1-degrading enzyme dipeptidyl peptidase 4. CONCLUSIONS: Combinatory therapy with SVPs and CSCs may complementarily help the repair of infarcted hearts.
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Infarto del Miocardio/cirugía , Miocardio/patología , Miocitos Cardíacos/trasplante , Neovascularización Fisiológica , Pericitos/trasplante , Regeneración , Trasplante de Células Madre , Proteínas Angiogénicas/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Fibrosis , Hemodinámica , Humanos , Ratones SCID , Contracción Miocárdica , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Comunicación Paracrina , Pericitos/metabolismo , Fenotipo , Recuperación de la Función , Vena Safena/citología , Factores de Tiempo , Remodelación VentricularRESUMEN
OBJECTIVE: We investigated the association between the functional, epigenetic, and expressional profile of human adventitial progenitor cells (APCs) and therapeutic activity in a model of limb ischemia. APPROACH AND RESULTS: Antigenic and functional features were analyzed throughout passaging in 15 saphenous vein (SV)-derived APC lines, of which 10 from SV leftovers of coronary artery bypass graft surgery and 5 from varicose SV removal. Moreover, 5 SV-APC lines were transplanted (8×10(5) cells, IM) in mice with limb ischemia. Blood flow and capillary and arteriole density were correlated with functional characteristics and DNA methylation/expressional markers of transplanted cells. We report successful expansion of tested lines, which reached the therapeutic target of 30 to 50 million cells in ≈10 weeks. Typical antigenic profile, viability, and migratory and proangiogenic activities were conserved through passaging, with low levels of replicative senescence. In vivo, SV-APC transplantation improved blood flow recovery and revascularization of ischemic limbs. Whole genome screening showed an association between DNA methylation at the promoter or gene body level and microvascular density and to a lesser extent with blood flow recovery. Expressional studies highlighted the implication of an angiogenic network centered on the vascular endothelial growth factor receptor as a predictor of microvascular outcomes. FLT-1 gene silencing in SV-APCs remarkably reduced their ability to form tubes in vitro and support tube formation by human umbilical vein endothelial cells, thus confirming the importance of this signaling in SV-APC angiogenic function. CONCLUSIONS: DNA methylation landscape illustrates different therapeutic activities of human APCs. Epigenetic screening may help identify determinants of therapeutic vasculogenesis in ischemic disease.
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Adventicia/trasplante , Metilación de ADN , Epigénesis Genética , Isquemia/cirugía , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , Vena Safena/trasplante , Trasplante de Células Madre , Células Madre/fisiología , Adventicia/citología , Animales , Velocidad del Flujo Sanguíneo , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Miembro Posterior , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Isquemia/genética , Isquemia/fisiopatología , Ratones , Neovascularización Fisiológica/genética , Recuperación de la Función , Flujo Sanguíneo Regional , Vena Safena/citología , Células Madre/metabolismo , Factores de TiempoRESUMEN
Reparative response by bone marrow (BM)-derived progenitor cells (PCs) to ischemia is a multistep process that comprises the detachment from the BM endosteal niche through activation of osteoclasts and proteolytic enzymes (such as matrix metalloproteinases (MMPs)), mobilization to the circulation, and homing to the injured tissue. We previously showed that intramyocardial nerve growth factor gene transfer (NGF-GT) promotes cardiac repair following myocardial infarction (MI) in mice. Here, we investigate the impact of cardiac NGF-GT on postinfarction BM-derived PCs mobilization and homing at different time points after adenovirus-mediated NGF-GT in mice. Immunohistochemistry and flow cytometry newly illustrate the temporal profile of osteoclast and activation of MMP9, PCs expansion in the BM, and liberation/homing to the injured myocardium. NGF-GT amplified these responses and increased the BM levels of active osteoclasts and MMP9, which were not observed in MMP9-deficient mice. Taken together, our results suggest a novel role for NGF in BM-derived PCs mobilization/homing following MI.
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Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/citología , Infarto del Miocardio/genética , Miocardio/patología , Factor de Crecimiento Nervioso/metabolismo , Adenoviridae/genética , Animales , Trasplante de Médula Ósea , Regulación de la Expresión Génica , Técnicas de Transferencia de Gen , Vectores Genéticos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Factor de Crecimiento Nervioso/genética , Osteoclastos/citologíaRESUMEN
OBJECTIVE: Diabetes mellitus causes bone marrow (BM) microangiopathy. This study aimed to investigate the mechanisms responsible for BM endothelial dysfunction in diabetes mellitus. METHODS AND RESULTS: The analysis of differentially expressed transcripts in BM endothelial cells (BMECs) from type-1 diabetic and nondiabetic mice showed an effect of diabetes mellitus on signaling pathways controlling cell death, migration, and cytoskeletal rearrangement. Type-1 diabetic-BMECs displayed high reactive oxygen species levels, increased expression and activity of RhoA and its associated protein kinases Rho-associated kinase 1/Rho-associated kinase 2, and reduced Akt phosphorylation/activity. Likewise, diabetes mellitus impaired Akt-related BMEC functions, such as migration, network formation, and angiocrine factor-releasing activity, and increased vascular permeability. Moreover, high glucose disrupted BMEC contacts through Src tyrosine kinase phosphorylation of vascular endothelial cadherin. These alterations were prevented by constitutively active Akt (myristoylated Akt), Rho-associated kinase inhibitor Y-27632, and Src inhibitors. Insulin replacement restored BMEC abundance, as assessed by flow cytometry analysis of the endothelial marker MECA32, and endothelial barrier function in BM of type-1 diabetic mice. CONCLUSIONS: Redox-dependent activation of RhoA/Rho-associated kinase and Src/vascular endothelial cadherin signaling pathways, together with Akt inactivation, contribute to endothelial dysfunction in diabetic BM. Metabolic control is crucial for maintenance of endothelial cell homeostasis and endothelial barrier function in BM of diabetic mice.
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Células de la Médula Ósea/enzimología , Permeabilidad Capilar , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Células Endoteliales/enzimología , Transducción de Señal , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Superficie/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Cadherinas/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular , Células Cultivadas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/genética , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/enzimología , Angiopatías Diabéticas/genética , Implantes de Medicamentos , Células Endoteliales/efectos de los fármacos , Citometría de Flujo , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Masculino , Ratones , Oxidación-Reducción , Estrés Oxidativo , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/genética , Proteína de Unión al GTP rhoA/genética , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
OBJECTIVE: To test the therapeutic activity of perivascular transplantation of encapsulated human mesenchymal stem cells (MSCs) in an immunocompetent mouse model of limb ischemia. APPROACH AND RESULTS: CD1 mice underwent unilateral limb ischemia, followed by randomized treatment with vehicle, alginate microbeads (MBs), MB-encapsulated MSCs (MB-MSCs), or MB-MSCs engineered with glucagon-like peptide-1. Treatments were applied directly in the perivascular space around the femoral artery. Laser Doppler and fluorescent microsphere assessment of blood flow showed a marked improvement of perfusion in the MB-MSCs and MB-MSCs engineered with glucagon-like peptide-1 groups, which was associated with increased foot salvage particularly in MB-MSCs engineered with glucagon-like peptide-1-treated mice. Histological analysis revealed increased capillary and arteriole density in limb muscles of the 2 MSC groups. Furthermore, MB-MSCs engineered with glucagon-like peptide-1 and, to a lesser extent, MB-MSC treatment increased functional arterial collaterals alongside the femoral artery occlusion. Analysis of expressional changes in ischemic muscles showed that MB-MSC transplantation activates a proangiogenic signaling pathway centered on vascular endothelial growth factor A. In contrast, intramuscular MB-MSCs caused inflammatory reaction, but no improvement of reparative vascularization. Importantly, nonencapsulated MSCs were ineffective either by intramuscular or perivascular route. CONCLUSIONS: Perivascular delivery of encapsulated MSCs helps postischemic reperfusion. This novel biological bypass method might be useful in patients not amenable to conventional revascularization approaches.
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Isquemia/fisiopatología , Isquemia/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Neovascularización Fisiológica/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Modelos Animales de Enfermedad , Estudios de Factibilidad , Femenino , Arteria Femoral/fisiología , Miembro Posterior/irrigación sanguínea , Humanos , Isquemia/metabolismo , Flujometría por Láser-Doppler , Recuperación del Miembro/métodos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Ratones , Comunicación Paracrina/fisiología , Distribución Aleatoria , Flujo Sanguíneo Regional/fisiología , Trasplante HeterólogoRESUMEN
BACKGROUND: Pain triggers a homeostatic alarm reaction to injury. It remains unknown, however, whether nociceptive signaling activated by ischemia is relevant for progenitor cells (PC) release from bone marrow. To this end, we investigated the role of the neuropeptide substance P (SP) and cognate neurokinin 1 (NK1) nociceptor in PC activation and angiogenesis during ischemia in mice and in human subjects. METHODS AND RESULTS: The mouse bone marrow contains sensory fibers and PC that express SP. Moreover, SP-induced migration provides enrichment for PC that express NK1 and promote reparative angiogenesis after transplantation in a mouse model of limb ischemia. Acute myocardial infarction and limb ischemia increase SP levels in peripheral blood, decrease SP levels in bone marrow, and stimulate the mobilization of NK1-expressing PC, with these effects being abrogated by systemic administration of the opioid receptor agonist morphine. Moreover, bone marrow reconstitution with NK1-knockout cells results in depressed PC mobilization, delayed blood flow recovery, and reduced neovascularization after ischemia. We next asked whether SP is instrumental to PC mobilization and homing in patients with ischemia. Human PC express NK1, and SP-induced migration provides enrichment for proangiogenic PC. Patients with acute myocardial infarction show high circulating levels of SP and NK1-positive cells that coexpress PC antigens, such as CD34, KDR, and CXCR4. Moreover, NK1-expressing PC are abundant in infarcted hearts but not in hearts that developed an infarct after transplantation. CONCLUSIONS: Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.
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Isquemia/fisiopatología , Neovascularización Fisiológica , Nocicepción/fisiología , Transducción de Señal/fisiología , Células Madre/fisiología , Sustancia P/fisiología , Animales , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Receptores de Neuroquinina-1/fisiologíaRESUMEN
Pericytes are a heterogeneous population of cells located in the blood vessel wall. They were first identified in the 19th century by Rouget, however their biological role and potential for drug targeting have taken time to be recognised. Isolation of pericytes from several different tissues has allowed a better phenotypic and functional characterization. These findings revealed a tissue-specific, multi-functional group of cells with multilineage potential. Given this emerging evidence, pericytes have acquired specific roles in pathobiological events in vascular diseases. In this review article, we will provide a compelling overview of the main diseases in which pericytes are involved, from well-established mechanisms to the latest findings. Pericyte involvement in diabetes and cancer will be discussed extensively. In the last part of the article we will review therapeutic approaches for these diseases in light of the recently acquired knowledge. To unravel pericyte-related vascular pathobiological events is pivotal not only for more tailored treatments of disease but also to establish pericytes as a therapeutic tool.
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Isquemia/fisiopatología , Pericitos/citología , Enfermedades Vasculares/fisiopatología , Animales , Diabetes Mellitus/fisiopatología , Diabetes Mellitus/terapia , Humanos , Isquemia/terapia , Terapia Molecular Dirigida , Neoplasias/patología , Neoplasias/terapia , Enfermedades Vasculares/terapiaRESUMEN
Patients with type 1 diabetes have lower bone mineral density and higher risk of fractures. The role of osteoblasts in diabetes-related osteoporosis is well acknowledged whereas the role of osteoclasts (OCLs) is still unclear. We hypothesize that OCLs participate in pathological bone remodeling. We conducted studies in animals (streptozotocin-induced type 1 diabetic mice) and cellular models to investigate canonical and non-canonical mechanisms underlying excessive OCL activation. Diabetic mice show an increased number of active OCLs. In vitro studies demonstrate the involvement of acidosis in OCL activation and the implication of transient receptor potential cation channel subfamily V member 1 (TRPV1). In vivo studies confirm the establishment of local acidosis in the diabetic bone marrow (BM) as well as the ineffectiveness of insulin in correcting the pH variation and osteoclast activation. Conversely, treatment with TRPV1 receptor antagonists re-establishes a physiological OCL availability. These data suggest that diabetes causes local acidosis in the BM that in turn increases osteoclast activation through the modulation of TRPV1. The use of clinically available TRPV1 antagonists may provide a new means to combat bone problems associated with diabetes.
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Acidosis/complicaciones , Diabetes Mellitus Experimental/complicaciones , Osteogénesis , Osteoporosis/etiología , Osteoporosis/fisiopatología , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Humanos , RatonesRESUMEN
UNLABELLED: Significance: Patients with diabetes mellitus suffer an excess of cardiovascular complications and recover worse from them as compared with their nondiabetic peers. It is well known that microangiopathy is the cause of renal damage, blindness, and heart attacks in patients with diabetes. This review highlights molecular deficits in stem cells and a supporting microenvironment, which can be traced back to oxidative stress and ultimately reduce stem cells therapeutic potential in diabetic patients. RECENT ADVANCES: New research has shown that increased oxidative stress contributes to inducing microangiopathy in bone marrow (BM), the tissue contained inside the bones and the main source of stem cells. These precious cells not only replace old blood cells but also exert an important reparative function after acute injuries and heart attacks. CRITICAL ISSUES: The starvation of BM as a consequence of microangiopathy can lead to a less efficient healing in diabetic patients with ischemic complications. Furthermore, stem cells from a patient's BM are the most used in regenerative medicine trials to mend hearts damaged by heart attacks. FUTURE DIRECTIONS: A deeper understanding of redox signaling in BM stem cells will lead to new modalities for preserving local and systemic homeostasis and to more effective treatments of diabetic cardiovascular complications.
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Médula Ósea/metabolismo , Microambiente Celular , Diabetes Mellitus/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Médula Ósea/patología , Diferenciación Celular , Supervivencia Celular/genética , Senescencia Celular , Complicaciones de la Diabetes , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Diabetes Mellitus Experimental , Endotelio/metabolismo , Endotelio/patología , Hematopoyesis/genética , Homeostasis , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Estrés Oxidativo/genética , Transducción de SeñalRESUMEN
AIMS: Vascular wall-resident progenitor cells hold great promise for cardiovascular regenerative therapy. This study evaluates the impact of oxidative stress on the viability and functionality of adventitia-derived progenitor cells (APCs) from vein remnants of coronary artery bypass graft (CABG) surgery. We also investigated the antioxidant enzymes implicated in the resistance of APCs to oxidative stress-induced damage and the effect of interfering with one of them, the extracellular superoxide dismutase (EC-SOD/SOD3), on APC therapeutic action in a model of peripheral ischemia. RESULTS: After exposure to hydrogen peroxide, APCs undergo apoptosis to a smaller extent than endothelial cells (ECs). This was attributed to up-regulation of antioxidant enzymes, especially SODs and catalase. Pharmacological inhibition of SODs increases reactive oxygen species (ROS) levels in APCs and impairs their survival. Likewise, APC differentiation results in SOD down-regulation and ROS-induced apoptosis. Oxidative stress increases APC migratory activity, while being inhibitory for ECs. In addition, oxidative stress does not impair APC capacity to promote angiogenesis in vitro. In a mouse limb ischemia model, an injection of naïve APCs, but not SOD3-silenced APCs, helps perfusion recovery and neovascularization, thus underlining the importance of this soluble isoform in protection from ischemia. INNOVATION: This study newly demonstrates that APCs are endowed with enhanced detoxifier and antioxidant systems and that SOD3 plays an important role in their therapeutic activity in ischemia. CONCLUSIONS: APCs from vein remnants of CABG patients express antioxidant defense mechanisms, which enable them to resist stress. These properties highlight the potential of APCs in cardiovascular regenerative medicine.
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Adventicia/citología , Antioxidantes/farmacología , Isquemia/metabolismo , Isquemia/terapia , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Animales , Antígenos de Superficie/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación hacia Abajo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Extremidades/irrigación sanguínea , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Silenciador del Gen , Humanos , Inmunofenotipificación , Isquemia/genética , Masculino , Ratones , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , Células Madre/citología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
Diabetes mellitus is considered a cardiovascular disease owing to its prevalent association with cardiovascular morbidity and mortality. Cardiovascular events are not only more frequent but also complicated with more severe outcomes in diabetic patients as compared with non-diabetic patients. One mechanism accounting for this difference consists of the impairment of the regenerative cellular machinery, which contributes to tissue healing. Recent evidence indicates the contribution of resident progenitor cells in post-ischemic tissue remodeling. In addition, a wide spectrum of cells from distant sources, including the bone marrow, is attracted and home to the healing tissue. Diabetes affects the process of mobilization and recruitment as well as intrinsic functional properties of bone marrow-derived progenitor cells. This review highlights current evidence for diabetes-induced damage of bone marrow hematopoietic progenitor cells in the endosteal and vascular niches.