Improved Survival, Vascular Differentiation and Wound Healing Potential of Stem Cells Co-Cultured with Endothelial Cells

In this study, we developed a methodology to improve the survival, vascular differentiation and regenerative potential of umbilical cord blood (UCB)-derived hematopoietic stem cells (CD34+ cells), by co-culturing the stem cells in a 3D fibrin gel with CD34+-derived endothelial cells (ECs). ECs differentiated from CD34+ cells appear to have superior angiogenic properties to fully differentiated ECs, such as human umbilical vein endothelial cells (HUVECs). Our results indicate that the pro-survival effect of CD34+-derived ECs on CD34+ cells is mediated, at least in part, by bioactive factors released from ECs. This effect likely involves the secretion of novel cytokines, including interleukin-17 (IL-17) and interleukin-10 (IL-10), and the activation of the ERK 1/2 pathway in CD34+ cells. We also show that the endothelial differentiation of CD34+ cells in co-culture with CD34+-derived ECs is mediated by a combination of soluble and insoluble factors. The regenerative potential of this co-culture system was demonstrated in a chronic wound diabetic animal model. The co-transplantation of CD34+ cells with CD34+-derived ECs improved the wound healing relatively to controls, by decreasing the inflammatory reaction and increasing the neovascularization of the wound.

• Publication year

  2011

• Venue

  PLoS ONE

• Publication date

  2011-01-24

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1371/journal.pone.0016114PMID 21283630PMCID 3026015
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Paracrine effects of CD34 progenitor cells on angiogenic endothelial sprouting.

  2010cited by this paper
• Fibrin gels and their clinical and bioengineering applications

  2009cited by this paper
• Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors.

  2009cited by this paper
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  2009cited by this paper
• Human CD133+ Progenitor Cells Promote the Healing of Diabetic Ischemic Ulcers by Paracrine Stimulation of Angiogenesis and Activation of Wnt Signaling

  2009influential reference
• Human mesenchymal stem cells express vascular cell phenotypes upon interaction with endothelial cell matrix

  2009cited by this paper
• Inflammation and neuropeptides: the connection in diabetic wound healing

  2009cited by this paper
• Impaired in vivo vasculogenic potential of endothelial progenitor cells in comparison to human umbilical vein endothelial cells in a spheroid‐based implantation model

  2009influential reference
• Thrombin bound to a fibrin clot confers angiogenic and haemostatic properties on endothelial progenitor cells

  2008cited by this paper
• Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing

  2008cited by this paper
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  2008cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
• Wound healing and its impairment in the diabetic foot.

  2005cited by this paper
• The global burden of diabetic foot disease.

  2005cited by this paper
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  2005cited by this paper
• Anti-inflammatory Effects of Human Cord Blood Cells in a Rat Model of Stroke

  2005cited by this paper
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  2005cited by this paper
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  2004cited by this paper
• Interleukin-17 family members and inflammation.

  2004cited by this paper
• Interleukin-17 promotes angiogenesis and tumor growth.

  2003cited by this paper
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  2003cited by this paper
• Regulation of wound healing by growth factors and cytokines.

  2003cited by this paper
• CD34+ Blood Cells Accelerate Vascularization and Healing of Diabetic Mouse Skin Wounds

  2003cited by this paper
• VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism

  2002influential reference
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  2001cited by this paper
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  2001cited by this paper
• Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases.

  2000cited by this paper
• The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions – comparison to other cytokines and growth factors

  1998cited by this paper
• Cytokine and chemokine production by CD34+ haemopoietic progenitor cells: detection in single cells

  1997cited by this paper
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  1997cited by this paper
• Interleukin-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells.

  1996cited by this paper
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  1996cited by this paper
• TGF-beta 1, IL-10 and IL-4 differentially modulate the cytokine-induced expression of IL-6 and IL-8 in human endothelial cells.

  1996cited by this paper
• IL-10 inhibits cytokine production by activated macrophages.

  1991cited by this paper

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