Pre-Administration of PLX-R18 Cells Protects Mice from Radiation-Induced Hematopoietic Failure and Lethality

Abstract

Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded (PLX)-R18 is a 3D-expanded placenta-derived stromal cell product designated for the treatment of hematological disorders. These cells have been shown in vitro to secrete hematopoietic proteins, to stimulate colony formation, and to induce bone marrow migration. Previous studies in mice showed that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting hematopoiesis related proteins to enhance reconstitution of the hematopoietic system. We assessed the potential effect of prophylactic PLX-R18 treatment on H-ARS. PLX-R18 cells were administered intramuscularly to C57BL/6 mice, −1 and 3 days after (LD70/30) total body irradiation. PLX R18 treatment significantly increased survival after irradiation (p < 0.0005). In addition, peripheral blood and bone marrow (BM) cellularity were monitored at several time points up to 30 days. PLX-R18 treatment significantly increased the number of colony-forming hematopoietic progenitors in the femoral BM and significantly raised peripheral blood cellularity. PLX-R18 administration attenuated biomarkers of bone marrow aplasia (EPO, FLT3L), sepsis (SAA), and systemic inflammation (sP-selectin and E-selectin) and attenuated radiation-induced inflammatory cytokines/chemokines and growth factors, including G-CSF, MIP-1a, MIP-1b, IL-2, IL-6 and MCP-1, In addition, PLX-R18 also ameliorated radiation-induced upregulation of pAKT. Taken together, prophylactic PLX-R18 administration may serve as a protection measure, mitigating bone marrow failure symptoms and systemic inflammation in the H-ARS model.

PrC-210 Protects against Radiation-Induced Hematopoietic and Intestinal Injury in Mice and Reduces Oxidative Stress

“…It is well known that the hematopoietic system is extremely sensitive to ionizing radiation. In earlier studies, we showed that various classes of prophylactic agents (PLX-R18, CDX-301, GT3, BBT-059, Ex-RAD, JNJ-26366821) were able to rescue mice from lethality by suppressing gamma radiation-induced damage in the hematopoietic system [14,15,17,24,25]. In this report, our data indicate that oral, prophylactic administration of PrC-210 provided equal or better protection of mice from radiation-induced lethality by protecting their hematopoietic system.…”

“…A clonogenic assay was performed with cells harvested from femoral bone marrow, as described previously [14]. Sternal histopathology was carried out on the sterna fixed in 10% neutral-buffered formalin, as described previously [17]. The bone marrow cellularity was qualitatively evaluated within the sternebrae, and megakaryocytes were counted by averaging the number of cells per 10 (40× high-powered fields (HPFs).…”