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Reduction in the levels of circulating stem cells (CSCs) and endothelial progenitor cells (EPCs) predicts development or progression of microangiopathy and macroangiopathy in patients with type 2 diabetes (T2D). We tested whether treatment with sodium glucose cotransporter-2 (SGLT2) inhibitors affected the levels of CSCs and EPCs. A randomized trial of dapagliflozin vs placebo with open-label extension, and an open-label observational study of empagliflozin treatment. Tertiary referral diabetes outpatient clinic. Patients with T2D aged 18 to 75 years. Dapagliflozin at 10 mg vs placebo (n = 31); empagliflozin at 10 mg (n = 15). We measured CSCs (CD34+) and EPCs (CD34+KDR+) by flow cytometry at baseline, at 12 weeks, and after the extension period. After 12 weeks, CSCs declined nonsignificantly in the dapagliflozin group, remained stable in the placebo group, and the change from baseline was not significantly different between the two groups. EPCs declined nonsignificantly in the dapagliflozin group, increased nonsignificantly in the placebo group, and the change from baseline was significantly different between the two groups. After an open-label extension period of about 1.5 years, CSCs remained stable over time, whereas EPCs significantly increased in patients who received dapagliflozin. In all patients, irrespectively of treatment, EPCs increased significantly from baseline to the end of observation, concomitantly with improvement in HbA1c. In a cohort of 15 patients who received open-label empagliflozin for 12 weeks, CSCs declined nonsignificantly, whereas EPCs remained stable. SGLT2 inhibitors do not significantly increase CSCs or EPCs. Thus, cardiovascular protection by SGLT2 inhibitors may not directly involve stem/progenitor cells.

Abstract Compromised alveolar development and pulmonary vascular remodeling are hallmarks of pediatric lung diseases such as bronchopulmonary dysplasia (BPD) and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Although advances in surfactant therapy, corticosteroids, and antiinflammatory drugs have improved clinical management of preterm infants, those who suffer with severe vascular complications still lack viable treatment options. Paucity of the alveolar capillary network in ACDMPV causes respiratory distress and leads to mortality in a vast majority of infants with ACDMPV. The discovery of endothelial progenitor cells (EPCs) in 1997 brought forth the paradigm of postnatal vasculogenesis and hope for promoting vascularization in fragile patient populations, such as those with BPD and ACDMPV. The identification of diverse EPC populations, both hematopoietic and nonhematopoietic in origin, provided a need to identify progenitor cell–selective markers that are linked to progenitor properties needed to develop cell-based therapies. Focusing on the future potential of EPCs for regenerative medicine, this review will discuss various aspects of EPC biology, beginning with the identification of hematopoietic, nonhematopoietic, and tissue-resident EPC populations. We will review knowledge related to cell surface markers, signature gene expression, and key transcriptional regulators and will explore the translational potential of EPCs for cell-based therapy for BPD and ACDMPV. The ability to produce pulmonary EPCs from patient-derived induced pluripotent stem cells in vitro holds promise for restoring vascular growth and function in the lungs of patients with pediatric pulmonary disorders.

Transplantation of endothelial progenitor cells (EPCs) is a proven safe and effective method for treatment of cerebral ischemia in animal experiments. However, safety and efficacy need to be determined in clinical trials. We performed a two‐center, randomized, placebo‐controlled phase I/IIa trial with blinded outcome assessment on 18 patients with acute cerebral infarct within the middle cerebral artery territory, and followed for up to 4 years. Autologous ex vivo expanded EPCs were injected intravenously in the EPC group, and patients who received saline or autologous bone marrow stromal cells served as control groups. Mortality of any cause, adverse events, and new‐onset comorbidities were monitored. Changes in neurological deficits were assessed at different time points. We found no toxicity events or infusional or allergic reactions in any treated group. Three patients in the placebo group died during the 4‐year follow‐up. We found that the EPC group had fewer serious adverse events compared with the placebo‐controlled group, although there were no statistical differences in mortality among the three groups. Furthermore, there was no significant difference in neurological or functional improvement observed among the three groups, except for the Scandinavia Stroke Scale score at 3 months between the EPC group and placebo‐controlled group. Autologous transplantation of EPCs appears to improve long‐term safety in acute cerebral infarct patients, supporting the feasibility of this novel method for treatment of ischemic stroke (ClinicalTrials.gov: NCT01468064). Stem Cells Translational Medicine 2019;8:14–21

Background This phase II randomized controlled trial tested whether the intracarotid arterial administration (ICAA) of autologous CD34 + cells to patients within 14 ± 7 days after acute ischemic stroke (IS) could be safe and further improve short- and long-term outcomes. Methods Between January 2018 and March 2022, 28 consecutive patients were equally randomly allocated to the cell-treated group (CD34 + cells/3.0 × 10 7 /patient) or the control group (receiving optimal medical therapy). CD34 + cells were transfused into the ipsilateral brain infarct zone of cell-treated patients via the ICAA in the catheterization room. Results The results demonstrated 100% safety and success rates for the procedure, and no long-term tumorigenesis was observed in cell-treated patients. In cell-treated patients, the angiogenesis capacity of circulating endothelial progenitor cells (EPCs)/Matrigel was significantly greater after treatment than before treatment with granulocyte colony-stimulating factor (all p  < 0.001). Blood samples from the right internal jugular vein of the cell-treated patients presented significantly greater levels of the stromal cell-derived factor 1α/EPC at 5, 10 and 30 min compared with 0 min (all p  < 0.005). The National Institute of Health Stroke Scale scores were similar upon presentation, but a greater response was observed by Days 30 and 90 in the cell-treated group than in the control group. Tc-99 m brain perfusion was significantly greater at 180 days in the cell-treated group than in the control group ( p  = 0.046). The combined long-term end points (defined as death/recurrent stroke/or severe disability) were notably lower in the control group compared with the cell-treated group (14.3% vs. 50.0%, p  = 0.103). Conclusion Intracarotid transfusion of autologous CD34 + cells is safe and might improve long-term outcomes in patients with acute IS. Trial registration ISRCTN, ISRCTN15677760. Registered 23 April 2018- Retrospectively registered, https://doi.org/10.1186/ISRCTN15677760

Background Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control. Methods This study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45 dim CD34 + VEGFR-2 + and CD45 dim CD133 − CD34 + CD144 + respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill’s colonies). Results At baseline TG had lower cEPCs, PACs, CFU-Hills’ colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill’s colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill’s colonies with cECs. Conclusions Metformin has potential cardio-protective effect through improving cEPCs, CFU-Hill’s colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes. Trial registration ISRCTN26092132

Background Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population. Methods 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30–70 years old), HbA1c of 6.5–10%, CKD Stage 1–3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant. Results A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement. Conclusions In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015

Background Distraction osteogenesis (DO) is an effective but lengthy procedure to fully induce bone regeneration in large bone defects. Accumulating evidence supports the role of exosomes secreted by endothelial progenitor cells (EPC-Exos) in stimulating angiogenesis, which is closely coupled with osteogenesis. This study aimed to investigate whether EPC-Exos promote bone regeneration during DO in rats. Methods Exosomes were isolated from the supernatants of rat bone marrow EPCs via ultracentrifugation and characterized via transmission electron microscopy, tunable resistive pulse sensing analysis, and western blot analysis. Unilateral tibial DO models were generated using 68 Sprague-Dawley rats with a distraction rate of 0.5 mm per day for 10 days. After local injection of EPC-Exos into the distraction gaps after distraction, the therapeutic effects of EPC-Exos on bone regeneration and angiogenesis were assessed via X-ray, micro-computed tomography (micro-CT), and biomechanical and histological analyses. Pro-angiogenic effects and the potential mechanism underlying the effects of EPC-Exos on human umbilical vein endothelial cells were subsequently evaluated via in vitro assays including Cell Counting Kit-8, wound healing, tube formation, and western blot assays. Results EPC-Exos were spherical or cup-shaped vesicles ranging from 50 to 150 nm in diameter and expressed markers including CD9, Alix, and TSG101. X-ray, micro-CT, and histological analyses revealed that bone regeneration was markedly accelerated in rats treated with EPC-Exos. The distracted tibias from the Exos group also displayed enhanced mechanical properties. Moreover, vessel density was higher in the Exos group than in the control group. In addition, in vitro analyses revealed that EPC-Exos enhanced the proliferation, migration, and angiogenic capacity of endothelial cells in an miR-126-dependent manner. Further, EPC-Exos downregulated SPRED1 and activated Raf/ERK signaling. Conclusions The present results show that EPC-Exos accelerate bone regeneration during DO by stimulating angiogenesis, suggesting their use as a novel method to shorten the treatment duration of DO.

Self-assembled microvasculature from cocultures of endothelial cells (ECs) and stromal cells has significantly advanced efforts to vascularize engineered tissues by enhancing perfusion rates in vivo and producing investigative platforms for microvascular morphogenesis in vitro . However, to clinically translate prevascularized constructs, the issue of EC source must be resolved. Endothelial progenitor cells (EPCs) can be noninvasively supplied from the recipient through adult peripheral and umbilical cord blood, as well as derived from induced pluripotent stem cells, alleviating antigenicity issues. EPCs can also differentiate into all tissue endothelium, and have demonstrated potential for therapeutic vascularization. Yet, EPCs are not the standard EC choice to vascularize tissue constructs in vitro . Possible reasons include unresolved issues with EPC identity and characterization, as well as uncertainty in the selection of coculture, scaffold, and culture media combinations that promote EPC microvessel formation. This review addresses these issues through a summary of EPC vascular biology and the effects of tissue engineering design parameters upon EPC microvessel formation. Also included are perspectives to integrate EPCs with emerging technologies to produce functional, organotypic vascularized tissues.

Background Endothelial progenitor cell (EPC) differentiation is considered crucial for vascular repair. Vascular endothelial growth factor (VEGF) induces EPC differentiation, but the underlying mechanism of this phenomenon remains unclear. Connexin 43 (Cx43) is reported to be involved in the regulation of stem cell differentiation. Therefore, we sought to determine whether Cx43 is involved in VEGF-induced EPC differentiation and vascular repair. Methods Rat spleen-derived EPCs were cultured and treated with various concentrations of VEGF (0, 10, or 50 ng/mL), and the relationship between EPC differentiation and Cx43 expression was evaluated. Thereafter, fluorescence redistribution after photobleaching was performed to assess the relationship between adjacent EPC differentiation and Cx43-induced gap junction intercellular communication (GJIC). After carotid artery injury, EPCs pretreated with VEGF were injected into the tail veins, and the effects of Cx43 on vascular repair were evaluated. Results EPCs cultured with VEGF exhibited accelerated differentiation and increased expression of Cx43. However, inhibition of Cx43 expression using short interfering RNA (siRNA) attenuated EPC GJIC and consequent EPC differentiation. VEGF-pretreated EPC transplantation promoted EPC homing and reendothelialization, and inhibited neointimal formation. These effects were attenuated by siRNA inhibition of Cx43. Conclusions Our results from in vivo and in vitro experiments indicated that VEGF promotes EPC differentiation and vascular repair through Cx43.