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Vasoprotective effects of human CD34+ cells: towards clinical applications.

Kiernan TJ, Boilson BA, Witt TA, Dietz AB, Lerman A, Simari RD - J Transl Med (2009)

Bottom Line: Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 +/- 0.18, and 1.71 +/- 0.18 for CD34, and saline-treated vessels, respectively P < 0.05).Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 +/- 10.2, and 36.8 +/- 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05) Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury.These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. kiernan.thomas@mayo.edu

ABSTRACT

Background: The development of cell-based therapeutics for humans requires preclinical testing in animal models. The use of autologous animal products fails to address the efficacy of similar products derived from humans. We used a novel immunodeficient rat carotid injury model in order to determine whether human cells could improve vascular remodelling following acute injury.

Methods: Human CD34+ cells were separated from peripheral buffy coats using automatic magnetic cell separation. Carotid arterial injury was performed in male Sprague-Dawley nude rats using a 2F Fogarty balloon catheter. Freshly harvested CD34+ cells or saline alone was administered locally for 20 minutes by endoluminal instillation. Structural and functional analysis of the arteries was performed 28 days later.

Results: Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 +/- 0.18, and 1.71 +/- 0.18 for CD34, and saline-treated vessels, respectively P < 0.05). Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 +/- 10.2, and 36.8 +/- 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05)

Conclusion: Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury. These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

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Related in: MedlinePlus

Tracking of delivered cells. Light microscopy cross section (20×) showing neointima formation in immunodeficient rat carotid 4 weeks after balloon injury (A). CM-Dil-labeled human CD34+ cells stain red under fluorescent microscope (20×) within intima and media of carotid 4 weeks after balloon injury (B). IEL = Internal elastic lamina, EEL = external elastic lamina.
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Figure 2: Tracking of delivered cells. Light microscopy cross section (20×) showing neointima formation in immunodeficient rat carotid 4 weeks after balloon injury (A). CM-Dil-labeled human CD34+ cells stain red under fluorescent microscope (20×) within intima and media of carotid 4 weeks after balloon injury (B). IEL = Internal elastic lamina, EEL = external elastic lamina.

Mentions: To determine whether delivery of cells resulted in any cell retention for the 4 weeks following delivery, carotid sections were examined under fluorescence microscopy for detection of CM-DiI-labeled cells. Specific red fluorescence identified the presence of labeled human CD34+ cells within the neointima, media, and adventitia of injured segments. No labeled cells were identified in uninjured control arteries. In animals receiving human CD34+ cells, only 12.5% of carotid sections demonstrated fluorescent luminal endothelial cells at 4 weeks. Labeled cells were seen in the media (Figure 2) but also in the neointima and adventitia under fluorescent microscopy. This finding is very consistent with previous findings in circulation-derived cells [1] and suggests a paracrine mechanism for these effects.


Vasoprotective effects of human CD34+ cells: towards clinical applications.

Kiernan TJ, Boilson BA, Witt TA, Dietz AB, Lerman A, Simari RD - J Transl Med (2009)

Tracking of delivered cells. Light microscopy cross section (20×) showing neointima formation in immunodeficient rat carotid 4 weeks after balloon injury (A). CM-Dil-labeled human CD34+ cells stain red under fluorescent microscope (20×) within intima and media of carotid 4 weeks after balloon injury (B). IEL = Internal elastic lamina, EEL = external elastic lamina.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724497&req=5

Figure 2: Tracking of delivered cells. Light microscopy cross section (20×) showing neointima formation in immunodeficient rat carotid 4 weeks after balloon injury (A). CM-Dil-labeled human CD34+ cells stain red under fluorescent microscope (20×) within intima and media of carotid 4 weeks after balloon injury (B). IEL = Internal elastic lamina, EEL = external elastic lamina.
Mentions: To determine whether delivery of cells resulted in any cell retention for the 4 weeks following delivery, carotid sections were examined under fluorescence microscopy for detection of CM-DiI-labeled cells. Specific red fluorescence identified the presence of labeled human CD34+ cells within the neointima, media, and adventitia of injured segments. No labeled cells were identified in uninjured control arteries. In animals receiving human CD34+ cells, only 12.5% of carotid sections demonstrated fluorescent luminal endothelial cells at 4 weeks. Labeled cells were seen in the media (Figure 2) but also in the neointima and adventitia under fluorescent microscopy. This finding is very consistent with previous findings in circulation-derived cells [1] and suggests a paracrine mechanism for these effects.

Bottom Line: Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 +/- 0.18, and 1.71 +/- 0.18 for CD34, and saline-treated vessels, respectively P < 0.05).Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 +/- 10.2, and 36.8 +/- 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05) Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury.These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. kiernan.thomas@mayo.edu

ABSTRACT

Background: The development of cell-based therapeutics for humans requires preclinical testing in animal models. The use of autologous animal products fails to address the efficacy of similar products derived from humans. We used a novel immunodeficient rat carotid injury model in order to determine whether human cells could improve vascular remodelling following acute injury.

Methods: Human CD34+ cells were separated from peripheral buffy coats using automatic magnetic cell separation. Carotid arterial injury was performed in male Sprague-Dawley nude rats using a 2F Fogarty balloon catheter. Freshly harvested CD34+ cells or saline alone was administered locally for 20 minutes by endoluminal instillation. Structural and functional analysis of the arteries was performed 28 days later.

Results: Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 +/- 0.18, and 1.71 +/- 0.18 for CD34, and saline-treated vessels, respectively P < 0.05). Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 +/- 10.2, and 36.8 +/- 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05)

Conclusion: Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury. These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

Show MeSH
Related in: MedlinePlus