Circulatory rejuvenated epcs derived from paod patients treated by cd34+ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia

Yin Chia Chen; Jiunn Jye Sheu; John Y. Chiang; Pei Lin Shao; Shun Cheng Wu; Pei Hsun Sung; Yi Chen Li; Yi Ling Chen; Tien Hung Huang; Kuan Hung Chen; Hon Kan Yip

doi:10.3390/ijms21217887

Circulatory rejuvenated epcs derived from paod patients treated by cd34⁺ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia

Yin Chia Chen, Jiunn Jye Sheu, John Y. Chiang, Pei Lin Shao, Shun Cheng Wu, Pei Hsun Sung, Yi Chen Li, Yi Ling Chen, Tien Hung Huang, Kuan Hung Chen, Hon Kan Yip^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

8 Scopus citations

Abstract

This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 10⁵) derived from PAOD patient’s circulatory blood prior to CD34⁺ cell and HBO treatment (EPC^Pr-T ) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 10⁵) derived from PAOD patient’s circulatory blood after CD34⁺ cell and HBO treatment (EPC^Af-T ) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 (p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-ß) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31⁺/vWF⁺ ) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.

Original language	English
Article number	7887
Pages (from-to)	1-18
Number of pages	18
Journal	International Journal of Molecular Sciences
Volume	21
Issue number	21
DOIs	https://doi.org/10.3390/ijms21217887
State	Published - 01 11 2020

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Angiogenesis
Critical limb ischemia
Endothelial progenitor cells
Hyperbaric oxygen therapy
Nude mice

Access to Document

10.3390/ijms21217887

Cite this

Chen, Y. C., Sheu, J. J., Chiang, J. Y., Shao, P. L., Wu, S. C., Sung, P. H., Li, Y. C., Chen, Y. L., Huang, T. H., Chen, K. H., & Yip, H. K. (2020). Circulatory rejuvenated epcs derived from paod patients treated by cd34⁺ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia. International Journal of Molecular Sciences, 21(21), 1-18. Article 7887. https://doi.org/10.3390/ijms21217887

@article{1261d125cd374ead8470c7747c645016,

title = "Circulatory rejuvenated epcs derived from paod patients treated by cd34+ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia",

abstract = "This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 105) derived from PAOD patient{\textquoteright}s circulatory blood prior to CD34+ cell and HBO treatment (EPCPr-T ) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 105) derived from PAOD patient{\textquoteright}s circulatory blood after CD34+ cell and HBO treatment (EPCAf-T ) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 (p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-{\ss}) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31+/vWF+ ) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.",

keywords = "Angiogenesis, Critical limb ischemia, Endothelial progenitor cells, Hyperbaric oxygen therapy, Nude mice",

author = "Chen, {Yin Chia} and Sheu, {Jiunn Jye} and Chiang, {John Y.} and Shao, {Pei Lin} and Wu, {Shun Cheng} and Sung, {Pei Hsun} and Li, {Yi Chen} and Chen, {Yi Ling} and Huang, {Tien Hung} and Chen, {Kuan Hung} and Yip, {Hon Kan}",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = nov,

day = "1",

doi = "10.3390/ijms21217887",

language = "英语",

volume = "21",

pages = "1--18",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "21",

}

Chen, YC, Sheu, JJ, Chiang, JY, Shao, PL, Wu, SC, Sung, PH, Li, YC, Chen, YL, Huang, TH, Chen, KH & Yip, HK 2020, 'Circulatory rejuvenated epcs derived from paod patients treated by cd34⁺ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia', International Journal of Molecular Sciences, vol. 21, no. 21, 7887, pp. 1-18. https://doi.org/10.3390/ijms21217887

Circulatory rejuvenated epcs derived from paod patients treated by cd34⁺ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia. / Chen, Yin Chia; Sheu, Jiunn Jye; Chiang, John Y. et al.
In: International Journal of Molecular Sciences, Vol. 21, No. 21, 7887, 01.11.2020, p. 1-18.

Research output: Contribution to journal › Journal Article › peer-review

TY - JOUR

T1 - Circulatory rejuvenated epcs derived from paod patients treated by cd34+ cells and hyperbaric oxygen therapy salvaged the nude mouse limb against critical ischemia

AU - Chen, Yin Chia

AU - Sheu, Jiunn Jye

AU - Chiang, John Y.

AU - Shao, Pei Lin

AU - Wu, Shun Cheng

AU - Sung, Pei Hsun

AU - Li, Yi Chen

AU - Chen, Yi Ling

AU - Huang, Tien Hung

AU - Chen, Kuan Hung

AU - Yip, Hon Kan

PY - 2020/11/1

Y1 - 2020/11/1

N2 - This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood prior to CD34+ cell and HBO treatment (EPCPr-T ) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood after CD34+ cell and HBO treatment (EPCAf-T ) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 (p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-ß) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31+/vWF+ ) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.

AB - This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood prior to CD34+ cell and HBO treatment (EPCPr-T ) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood after CD34+ cell and HBO treatment (EPCAf-T ) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 (p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-ß) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31+/vWF+ ) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.

KW - Angiogenesis

KW - Critical limb ischemia

KW - Endothelial progenitor cells

KW - Hyperbaric oxygen therapy

KW - Nude mice

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DO - 10.3390/ijms21217887

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