Electrophysiological and contractile evidence of the ability of human mesenchymal stromal cells to correct vascular malfunction in rats after ionizing irradiation.
The effect of intravenous administration of human mesenchymal stromal stem cells (hMSC) has been evaluated by means of large-conductance calcium-dependent potassium channel (BK(Ca)) activity measurements in thoracic aorta smooth muscle cells (SMC) obtained from non-fatal whole-body irradiated rats, using the patch clamp technique in whole-cell modification, and the standard acetylcholine (ACh) test to evaluate functional endothelium integrity using SM contractile recordings. Myofilament calcium sensitivity was estimated using simultaneous contractile recordings versus [Ca(2+)](i). Arterial blood was measured in intact and irradiated rats before and after hMSC administration. Stimulation of isolated SMC from the control group of animals with depolarizing voltage steps showed that outward K(+) currents sensitive to the BK(Ca) inhibitor paxilline were expressed. Outward currents in SMC obtained from irradiated animals were significantly reduced on the 30th day of post-irradiation. Irradiation led to a significant elevation in arterial blood pressure and reduced ACh-induced relaxation responses in irradiated rats as compared with the control group. Simultaneous measurements of contractile force and [Ca(2+)](i) showed that myofilament Ca(2+) sensitivity had increased following irradiation. Intravenously injected hMSC effectively restored BK(Ca) current and the amplitude of ACh-induced endothelium-dependent vasodilatation in vascular tissues obtained from post-irradiated rats. SMC obtained from irradiated rats treated with hMSC demonstrated a significantly increased paxilline-sensitive component of outward potassium currents, indicating that BK(Ca) activity had been restored. hMSC administration normalized increased blood pressure and myofilament Ca(2+) sensitivity in irradiated animals. When administered to healthy rats, hMSC were without effects on either of these. This study does not provide any immunohistochemical proof of hMSC engraftment in the host rats. PCR analysis showed that hMSCs were negative for hematopoietic cell markers and positive for hMSC markers. There were no clinical signs of graft-versus-host disease throughout the experimental period of 30 days. The data obtained suggest that hMSC demonstrate a clearly expressed ability to normalize vascular function damaged following irradiation, i.e. to reduce an elevated arterial blood pressure and myofilament Ca(2+) sensitivity, and to repair BK(Ca) function and endothelium-dependent relaxation in vascular tissues obtained from irradiated animals. Thus, hMSC seem to be worthwhile therapeutic approach in cases of ionizing irradiation accident or radiation beam therapy.
Soloviev
Anatoly
A
Department for Experimental Therapeutics, Institute of Pharmacology and Toxicology, Academy of Medical Science, 14 Eugene Pottier Str., 03057, Kiev, Ukraine. tonysolpharm@ukrpost.ua
Prudnikov
Igor
I
Tsyvkin
Vladimir
V
Tishkin
Sergey
S
Kyrychenko
Sergey
S
Zelensky
Sergey
S
Ivanova
Irina
I
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008875:Middle Aged; D011832:Radiation Injuries / Q000209:etiology / Q000503:physiopathology* / Q000601:surgery*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000209:etiology / Q000503:physiopathology* / Q000601:surgery*; D014916:Whole-Body Irradiation / Q000009:adverse effects*