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Therapeutic Effects of Umbilical Cord Blood Derived Mesenchymal Stem Cell-Conditioned Medium on Pulmonary Arterial Hypertension in Rats.

Lee JC, Cha CI, Kim DS, Choe SY - J Pathol Transl Med (2015)

Bottom Line: Compared with the control unconditioned media, CM infusion reduced the ventricular pressure, the right ventricle/(left ventricle+interventricular septum) ratio, and maintained respiratory function in the treated animals.Also, the number of interleukin 1α (IL-1α), chemokine (C-C motif) ligand 5 (CCL5), and tissue inhibitor of metalloproteinase 1 (TIMP-1)-positive cells increased in lung samples and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL)-positive cells decreased significantly in the CM treated animals.From our in vivo data in the rat model, the observed decreases in the TUNEL staining suggest a potential therapeutic benefit of the CM in ameliorating PAH-mediated lung tissue damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Life Sciences, Chungbuk National University, Cheongju, Korea.

ABSTRACT

Background: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) may have multiple therapeutic applications for cell based therapy including the treatment of pulmonary artery hypertension (PAH). As low survival rates and potential tumorigenicity of implanted cells could undermine the mesenchymal stem cell (MSC) cell-based therapy, we chose to investigate the use of conditioned medium (CM) from a culture of MSC cells as a feasible alternative.

Methods: CM was prepared by culturing hUCB-MSCs in three-dimensional spheroids. In a rat model of PAH induced by monocrotaline, we infused CM or the control unconditioned culture media via the tail-vein of 6-week-old Sprague-Dawley rats.

Results: Compared with the control unconditioned media, CM infusion reduced the ventricular pressure, the right ventricle/(left ventricle+interventricular septum) ratio, and maintained respiratory function in the treated animals. Also, the number of interleukin 1α (IL-1α), chemokine (C-C motif) ligand 5 (CCL5), and tissue inhibitor of metalloproteinase 1 (TIMP-1)-positive cells increased in lung samples and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL)-positive cells decreased significantly in the CM treated animals.

Conclusions: From our in vivo data in the rat model, the observed decreases in the TUNEL staining suggest a potential therapeutic benefit of the CM in ameliorating PAH-mediated lung tissue damage. Increased IL-1α, CCL5, and TIMP-1 levels may play important roles in this regard.

No MeSH data available.


Related in: MedlinePlus

Inflammatory cytokine expressions in the three groups. (A) To screen whether hUCB-MSCs-CM affect local production of inflammatory cytokines by lung cells in the three groups, a cytokine array is performed on lung homogenates. (B) TIMP-1, IL-1α, and CCL5 are higher in the CM group compared to the C and M groups, whereas CCL7 and VEGF are lower in the CM group compared to the M group. CINC-1, CINC-2a/b, CX3CL1 LIX, and LECAM-1 are higher in the C group compared to the M and CM groups. C group, control group (n = 7); M group, monocrotaline group (n=7); CM group, hUCB-MSCs-CM group (n=7). hUCB-MSCs-CM, conditioned medium from human umbilical-cord blood derived mesenchymal cells; CINC-1, cytokine-induced neutrophil chemoattractant-1; CINC-2a/b, cytokine-induced neutrophil chemoattractant-2a/b; CX3CL1, chemokine (C-X-C motif) ligand 1; LIX, lipopolysaccharide-induced CXC chemokine; LECAM-1, leukocyte endothelial cell adhesion molecule 1; CCL7, chemokine (C-C motif) ligand 7; TIMP-1, tissue inhibitor of metalloproteinase 1; VEGF, vascular endothelial growth factor; IL-1α, interleukin 1α. ap<.05 compared with the C group; b,cp<.05 compared with the M group.
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f1-jptm-2015-09-11: Inflammatory cytokine expressions in the three groups. (A) To screen whether hUCB-MSCs-CM affect local production of inflammatory cytokines by lung cells in the three groups, a cytokine array is performed on lung homogenates. (B) TIMP-1, IL-1α, and CCL5 are higher in the CM group compared to the C and M groups, whereas CCL7 and VEGF are lower in the CM group compared to the M group. CINC-1, CINC-2a/b, CX3CL1 LIX, and LECAM-1 are higher in the C group compared to the M and CM groups. C group, control group (n = 7); M group, monocrotaline group (n=7); CM group, hUCB-MSCs-CM group (n=7). hUCB-MSCs-CM, conditioned medium from human umbilical-cord blood derived mesenchymal cells; CINC-1, cytokine-induced neutrophil chemoattractant-1; CINC-2a/b, cytokine-induced neutrophil chemoattractant-2a/b; CX3CL1, chemokine (C-X-C motif) ligand 1; LIX, lipopolysaccharide-induced CXC chemokine; LECAM-1, leukocyte endothelial cell adhesion molecule 1; CCL7, chemokine (C-C motif) ligand 7; TIMP-1, tissue inhibitor of metalloproteinase 1; VEGF, vascular endothelial growth factor; IL-1α, interleukin 1α. ap<.05 compared with the C group; b,cp<.05 compared with the M group.

Mentions: A profile of the cytokines in the lung homogenates was made to investigate potential changes from hUCB-MSC-CM treatment (Fig. 1). Ten pro-inflammatory cytokines that included cytokine-induced neutrophil chemoattractant-1 (CINC-1), cytokine-induced neutrophil chemoattractant-2a/b (CINC-2a/b), chemokine (C-X-C motif) ligand 1 (CX3CL1), lipopolysaccharide-induced CXC chemokine (LIX), leukocyte endothelial cell adhesion molecule 1 (LECAM-1), chemokine (C-X-C motif) ligand 7, TIMP-1, vascular endothelial growth factor (VEGF), IL-1α, and CCL5 were examined in the C, M, and CM groups. CINC-1, CINC-2a/b, CX3CL1, LIX, LECAM-1, TIMP-1, and VEGF were lower in the M and CM groups, whereas TIMP-1, IL-1α, and CCL5 were higher in the CM group compared to the C and M groups. CCL7 was higher in the M group, whereas CCL7 was lower in the CM group compared to the M group (Fig. 1).


Therapeutic Effects of Umbilical Cord Blood Derived Mesenchymal Stem Cell-Conditioned Medium on Pulmonary Arterial Hypertension in Rats.

Lee JC, Cha CI, Kim DS, Choe SY - J Pathol Transl Med (2015)

Inflammatory cytokine expressions in the three groups. (A) To screen whether hUCB-MSCs-CM affect local production of inflammatory cytokines by lung cells in the three groups, a cytokine array is performed on lung homogenates. (B) TIMP-1, IL-1α, and CCL5 are higher in the CM group compared to the C and M groups, whereas CCL7 and VEGF are lower in the CM group compared to the M group. CINC-1, CINC-2a/b, CX3CL1 LIX, and LECAM-1 are higher in the C group compared to the M and CM groups. C group, control group (n = 7); M group, monocrotaline group (n=7); CM group, hUCB-MSCs-CM group (n=7). hUCB-MSCs-CM, conditioned medium from human umbilical-cord blood derived mesenchymal cells; CINC-1, cytokine-induced neutrophil chemoattractant-1; CINC-2a/b, cytokine-induced neutrophil chemoattractant-2a/b; CX3CL1, chemokine (C-X-C motif) ligand 1; LIX, lipopolysaccharide-induced CXC chemokine; LECAM-1, leukocyte endothelial cell adhesion molecule 1; CCL7, chemokine (C-C motif) ligand 7; TIMP-1, tissue inhibitor of metalloproteinase 1; VEGF, vascular endothelial growth factor; IL-1α, interleukin 1α. ap<.05 compared with the C group; b,cp<.05 compared with the M group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4696528&req=5

f1-jptm-2015-09-11: Inflammatory cytokine expressions in the three groups. (A) To screen whether hUCB-MSCs-CM affect local production of inflammatory cytokines by lung cells in the three groups, a cytokine array is performed on lung homogenates. (B) TIMP-1, IL-1α, and CCL5 are higher in the CM group compared to the C and M groups, whereas CCL7 and VEGF are lower in the CM group compared to the M group. CINC-1, CINC-2a/b, CX3CL1 LIX, and LECAM-1 are higher in the C group compared to the M and CM groups. C group, control group (n = 7); M group, monocrotaline group (n=7); CM group, hUCB-MSCs-CM group (n=7). hUCB-MSCs-CM, conditioned medium from human umbilical-cord blood derived mesenchymal cells; CINC-1, cytokine-induced neutrophil chemoattractant-1; CINC-2a/b, cytokine-induced neutrophil chemoattractant-2a/b; CX3CL1, chemokine (C-X-C motif) ligand 1; LIX, lipopolysaccharide-induced CXC chemokine; LECAM-1, leukocyte endothelial cell adhesion molecule 1; CCL7, chemokine (C-C motif) ligand 7; TIMP-1, tissue inhibitor of metalloproteinase 1; VEGF, vascular endothelial growth factor; IL-1α, interleukin 1α. ap<.05 compared with the C group; b,cp<.05 compared with the M group.
Mentions: A profile of the cytokines in the lung homogenates was made to investigate potential changes from hUCB-MSC-CM treatment (Fig. 1). Ten pro-inflammatory cytokines that included cytokine-induced neutrophil chemoattractant-1 (CINC-1), cytokine-induced neutrophil chemoattractant-2a/b (CINC-2a/b), chemokine (C-X-C motif) ligand 1 (CX3CL1), lipopolysaccharide-induced CXC chemokine (LIX), leukocyte endothelial cell adhesion molecule 1 (LECAM-1), chemokine (C-X-C motif) ligand 7, TIMP-1, vascular endothelial growth factor (VEGF), IL-1α, and CCL5 were examined in the C, M, and CM groups. CINC-1, CINC-2a/b, CX3CL1, LIX, LECAM-1, TIMP-1, and VEGF were lower in the M and CM groups, whereas TIMP-1, IL-1α, and CCL5 were higher in the CM group compared to the C and M groups. CCL7 was higher in the M group, whereas CCL7 was lower in the CM group compared to the M group (Fig. 1).

Bottom Line: Compared with the control unconditioned media, CM infusion reduced the ventricular pressure, the right ventricle/(left ventricle+interventricular septum) ratio, and maintained respiratory function in the treated animals.Also, the number of interleukin 1α (IL-1α), chemokine (C-C motif) ligand 5 (CCL5), and tissue inhibitor of metalloproteinase 1 (TIMP-1)-positive cells increased in lung samples and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL)-positive cells decreased significantly in the CM treated animals.From our in vivo data in the rat model, the observed decreases in the TUNEL staining suggest a potential therapeutic benefit of the CM in ameliorating PAH-mediated lung tissue damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Life Sciences, Chungbuk National University, Cheongju, Korea.

ABSTRACT

Background: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) may have multiple therapeutic applications for cell based therapy including the treatment of pulmonary artery hypertension (PAH). As low survival rates and potential tumorigenicity of implanted cells could undermine the mesenchymal stem cell (MSC) cell-based therapy, we chose to investigate the use of conditioned medium (CM) from a culture of MSC cells as a feasible alternative.

Methods: CM was prepared by culturing hUCB-MSCs in three-dimensional spheroids. In a rat model of PAH induced by monocrotaline, we infused CM or the control unconditioned culture media via the tail-vein of 6-week-old Sprague-Dawley rats.

Results: Compared with the control unconditioned media, CM infusion reduced the ventricular pressure, the right ventricle/(left ventricle+interventricular septum) ratio, and maintained respiratory function in the treated animals. Also, the number of interleukin 1α (IL-1α), chemokine (C-C motif) ligand 5 (CCL5), and tissue inhibitor of metalloproteinase 1 (TIMP-1)-positive cells increased in lung samples and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL)-positive cells decreased significantly in the CM treated animals.

Conclusions: From our in vivo data in the rat model, the observed decreases in the TUNEL staining suggest a potential therapeutic benefit of the CM in ameliorating PAH-mediated lung tissue damage. Increased IL-1α, CCL5, and TIMP-1 levels may play important roles in this regard.

No MeSH data available.


Related in: MedlinePlus