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Fig. 1 | Stem Cell Research & Therapy

Fig. 1

From: BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury

Fig. 1

BCN057 treatment at 24 h post-irradiation mitigates RIGS and improves survival in mice. a Chemical structure of BCN057 (3-[(Furan-2-ylmethyl)-amino]-2-(7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-6-methylimidazo[1,2-a]pyridin-1-ium). b Pharmacokinetics of a single injection of BCN057 90 mg/kg via s.c. administration in C57BL/6 mice. Cmax (obs) 1130.5 ng/mL, Tmax (obs) 2.0 h, Vss (expo) 15935.8 mL, CL (obs area) 700.075 mL/h. c Portal camera image demonstrating abdominal irradiation (AIR) exposure field (i) and BCN057 treatment schema (ii). A 3-cm area (indicated by the rectangular box) of the mouse containing the gastrointestinal tract was irradiated (irradiation field), while shielding the upper thorax, head, and neck, as well as the lower and upper extremities, and protecting a significant portion of the bone marrow, thus predominantly inducing radiation-induced gastrointestinal syndrome (RIGS). Mice exposed to AIR were treated with BCN057 (s.c.) (90 mg/kg body weight) at 24 h following irradiation and continued up to day 8 (single dose/day). d Kaplan-Meier survival analysis of C57BL/6 mice (n = 25/group) receiving vehicle, BCN057, or no treatment at 24 h after AIR (14 Gy, 15 Gy, or 16 Gy) and continued up to day 8. Mice receiving BCN057 after 14 Gy, 15 Gy, or 16 Gy AIR demonstrated 80%, 60%, and 40% survival, respectively, and they continued to survive beyond 60 days without any symptoms of gastroenteritis or any other health complications, whereas mice receiving vehicle or no treatment following AIR died within 15 days (p < 0.0003, p < 0.0004, and p < 0.0007, respectively, log-rank (Mantel-Cox) test). BCN057 or vehicle do not confer any toxicity to normal mice. e (i) Kaplan-Meier survival analysis of C57BL/6 mice (n = 25/group) exposed to partial body irradiation (PBI). Head, neck, and upper extremities were shielded to spare 40% of bone marrow (BM40%). The part of the body exposed to irradiation is indicated by a rectangular box. (ii) Mice receiving BCN057 at 24 h post-PBI demonstrated 70% survival compared with untreated controls (p < 0.0001 log-rank (Mantel-Cox) test). f H&E stained representative cross section of jejunum from C57BL/6 mice treated with BCN057 at 24 h post-AIR (upper panels). Note restitution of the epithelium in mice receiving BCN057 compared with irradiated controls. H&E stained representative transverse section of jejunum from C57BL/6 mice treated with BCN057 at 24 h post-AIR (middle panels). Note restitution of crypt villus structure in BCN057-treated mice. However, irradiated, untreated mice showed significant loss of crypts along with villi denudation. Representative Ki67 immunohistochemistry of mice jejunal sections (lower panels). Note the increase in Ki67-positive crypt cells in mice receiving BCN057 at 24 h after AIR (iv) compared with AIR controls (ii). g–i Histogram showing crypt depth and villi length (g), percentage of Ki67-positive crypt cells (h), and number of crypts per mm (i) in the jejunum. Irradiated mice receiving BCN057 at 24 h after AIR demonstrated an increase in crypt depth and villi length (*p < 0.0006), number of crypts (*p < 0.0004), and percentage of Ki67-positive crypt cells (*p < 0.0005) compared with irradiated controls. j Histogram demonstrating serum dextran level in C57BL/6 mice exposed to AIR and then treated with or without BCN057. Mice receiving BCN057 treatment demonstrated lower serum dextran levels, thereby suggesting restitution of epithelial integrity compared with irradiated untreated controls (*p < 0.004, n = 3 per group, unpaired t test, two-tailed). Unirradiated control mice and unirradiated BCN057 treated mice also showed lower serum dextran level compared with irradiated controls (*p < 0.006, *p < 0.005, unpaired t test, two-tailed)

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