Mitigation of Lethal Radiation Syndrome in Mice by Intramuscular Injection of 3D Cultured Adherent Human Placental Stromal Cells

Abstract

Exposure to high lethal dose of ionizing radiation results in acute radiation syndrome with deleterious systemic effects to different organs. A primary target is the highly sensitive bone marrow and the hematopoietic system. In the current study C3H/HeN mice were total body irradiated by 7.7 Gy. Twenty four hrs and 5 days after irradiation 2×106 cells from different preparations of human derived 3D expanded adherent placental stromal cells (PLX) were injected intramuscularly. Treatment with batches consisting of pure maternal cell preparations (PLX-Mat) increased the survival of the irradiated mice from ∼27% to 68% (P<0.001), while cell preparations with a mixture of maternal and fetal derived cells (PLX-RAD) increased the survival to ∼98% (P<0.0001). The dose modifying factor of this treatment for both 50% and 37% survival (DMF50 and DMF37) was∼1.23. Initiation of the more effective treatment with PLX-RAD injection could be delayed for up to 48 hrs after irradiation with similar effect. A delayed treatment by 72 hrs had lower, but still significantly effect (p<0.05). A faster recovery of the BM and improved reconstitution of all blood cell lineages in the PLX-RAD treated mice during the follow-up explains the increased survival of the cells treated irradiated mice. The number of CD45+/SCA1+ hematopoietic progenitor cells within the fast recovering population of nucleated BM cells in the irradiated mice was also elevated in the PLX-RAD treated mice. Our study suggests that IM treatment with PLX-RAD cells may serve as a highly effective “off the shelf” therapy to treat BM failure following total body exposure to high doses of radiation. The results suggest that similar treatments may be beneficial also for clinical conditions associated with severe BM aplasia and pancytopenia.

Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by an LPA 2 Receptor-Specific Nonlipid Agonist

“…DBIBB was effective in mitigating HEM-ARS in the TBI model when administration began up to 72 h postirradiation. There are few reports in the literature on radioprotective and radiomitigative compounds (Anzai, et al, 2013; Basile, et al, 2012; Berbee, et al, 2011; Burdelya, et al, 2008; Gaberman, et al, 2013; Gao, et al, 2012; Geiger, et al, 2012; Haydont, et al, 2007; Kim, et al, 2013; Saha, et al, 2011; Sridharan, et al, 2013; Wang, et al, 2013), however, most of these interventions lose efficacy when administered 24 h postinjury or they are efficacious only in treating single-organ injury. The effective protection we detected with delayed administration of DBIBB indicates that the initial tissue damage sustained during the first 72 postirradiation hours can be effectively treated.…”

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop

“…Briefly, C3H/HeN mice exposed to 7.7 Gy TBI were given an intramuscular injection of PLX-R18 at 24 h and 5 days postirradiation. Animals receiving the cells had improved survival, and more rapid recovery of the bone marrow and blood cell lineages (5). The mechanism of action of the protection could be linked to an observed mobilization of differentiated cells into the blood in treated animals.…”

“…ESCs, MSCs and progenitor cells and have been collected from various tissues, including bone marrow, adipose tissue, placenta, amniotic fluid, cord blood, vascular endothelium and gingival/dental tissue (1). Other cells and cell sources with potential for use as cellular therapies for radiation injury include fetal-derived cells (2), induced pluripotent stem cells (iPSCs) (3), umbilical cord blood (UCB) cells (4), placental-derived stromal fractions (5) and vascular endothelial cells (6–9). …”

“…One example is PLX-R18, a placentally-derived cellular product, which is being evaluated by Pluristem Therapeutics, Inc. in a phase I clinical trial to treat incomplete hematopoietic recovery after hematopoietic cell transplantation. These cells release factors that can improve bone marrow function, and have shown efficacy in minimizing ischemic damage (27), and as mitigators of radiation injury (5). Finally, in murine studies, adipose tissue-derived MSCs improved survival and reconstitution of multiple hematopoietic lineages when administered after radiation exposure (28).…”

Long-Term Effects of Stem Cells on Total-Body Irradiated Mice

“…Cell therapies to reconstitute failing organs, aside from the hematopietic bone marrow (BM) stem cells transplantation, by indefinitely replacing the affected cells in most cases are not highly practical. Multipotent mesenchymal stromal cells from different sources, mainly from the BM, cord blood and adipose tissues were proposed for regenerative medicine [1]. To obtain the primary human BM MMSC culture, the mononuclear cell fraction was isolated from bone marrow of healthy donors' iliac crest by centrifugation in Ficoll gradient.…”