A novel potential therapy for vascular diseases: blood-derived stem/progenitor cells specifically activated by dendritic cells

Diabetes Metab Res Rev. 2014 Oct;30(7):623-34. doi: 10.1002/dmrr.2543.

Abstract

Background: Vascular diseases are a major cause of morbidity and mortality, particularly in diabetic patients. Stem/progenitor cell treatments with bone marrow-derived cells show safety and promising outcomes, albeit not without some preprocedural adverse events related to cell collection and mobilization. We describe a novel technology for generating a therapeutic population (BGC101) of enriched endothelial progenitor cells (EPCs) from non-mobilized blood, using dendritic cells to specifically direct stem/progenitor cell activity in vitro.

Methods and results: Selected immature plasmacytoid and myeloid dendritic cells from 24 healthy and two diabetic donors were activated with anti-inflammatory and pro-angiogenic molecules to induce specific activation signals. Co-culturing of activated dendritic cells with stem/progenitor cells for 12-66 h generated 83.7 ± 7.4 × 10(6) BGC101 cells with 97% viability from 250 mL of blood. BGC101, comprising 52.4 ± 2.5% EPCs (expressing Ulex-lectin, AcLDL uptake, Tie2, vascular endothelial growth factor receptor 1 and 2, and CD31), 16.1 ± 1.9% stem/progenitor cells (expressing CD34 and CD184) and residual B and T helper cells, demonstrated angiogenic and stemness potential and secretion of interleukin-8, interleukin-10, vascular endothelial growth factor and osteopontin. When administered to immunodeficient mice with limb ischemia (n = 40), BGC101 yielded a high safety profile and significantly increased blood perfusion, capillary density and leg function after 21 days. Cell tracking and biodistribution showed that engraftment was restricted to the ischemic leg.

Conclusions: These observations provide preliminary evidence that alternatively activated dendritic cells can promote the generation of EPC-enriched stem/progenitor cells within a 1-day culture. The resulting product BGC101 has the potential for treatment of various vascular conditions such as coronary heart disease, stroke and peripheral ischemia.

Keywords: cardiovascular diseases; dendritic cells; diabetes complications; endothelial progenitor cells; ischemia; stem/progenitor cell therapy.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Blood Donors
  • Cell Communication / physiology*
  • Cell- and Tissue-Based Therapy / methods*
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / cytology*
  • Dendritic Cells / physiology
  • Dendritic Cells / transplantation*
  • Diabetes Mellitus / blood
  • Diabetic Angiopathies / therapy*
  • Disease Models, Animal
  • Endothelial Progenitor Cells / cytology*
  • Endothelial Progenitor Cells / physiology
  • Endothelial Progenitor Cells / transplantation*
  • Female
  • Hindlimb / blood supply
  • Humans
  • In Vitro Techniques
  • Ischemia / therapy
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Signal Transduction / physiology
  • Treatment Outcome
  • Young Adult