Research Article: Marrow Stromal Cell Infusion Rescues Hematopoiesis in Lethally Irradiated Mice despite Rapid Clearance after Infusion

Date Published: February 16, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Xiaodong Yang, Ilango Balakrishnan, Beverly Torok-Storb, Manoj M. Pillai.


Marrow stromal cells (MSCs, also termed mesenchymal stem cells) have been proposed as a promising cellular therapy for tissue injury including radiation-induced marrow failure, but evidence for a direct effect is lacking. To assess the effects of MSCs on survival after lethal irradiation, we infused syngeneic MSCs (either as immortalized MSCs clones or primary MSCs) intravenously into wild-type C57/Bl6 mice within 24 hours of lethal total body irradiation (TBI). Mice receiving either of the MSC preparations had significantly improved survival when compared to controls. In vivo imaging, immune histochemistry, and RT-PCR employed to detect MSCs indicated that the infused MSCs were predominantly localized to the lungs and rapidly cleared following infusion. Our results suggest that a single infusion of MSCs can improve survival after otherwise lethal TBI but the effect is not due to a direct interaction with, or contribution to, the damaged marrow by MSCs.

Partial Text

High-dose ionizing radiation causes damage to many organs, especially those with highly proliferative cells such as the bone marrow and the gastrointestinal tract [1, 2]. Bone marrow failure is often the cause of death following moderate-to-severe exposures to radiation [3]. Several pharmacologic agents especially cytokines such as granulocyte colony stimulating factor (GCSF), granulocyte monocyte colony stimulating factor (GMCSF), interleukin 3 (IL3), and thrombopoietin (TPO) have been shown in various experimental models to mitigate hematopoietic effects of radiation and are approved for clinical use in scenarios of radiation-induced aplasia [4–6]. The efficacy of these agents is, however, limited to intermediate dose ranges which do not result in complete marrow ablation. Exposure to higher doses that result in complete marrow ablation requires the transplantation of a new lympho-hematopoietic system from a suitable donor [7]. As such transplantations are impractical to be performed expeditiously following exposure to high-dose radiation (accidental or nuclear attacks), there is significant interest in improving the efficacy of pharmacological agents as mentioned above and explore novel agents with efficacy at doses higher than what cytokines are typically effective. “Off-the shelf” cellular therapies that can be expanded from a few initial cells, frozen, and thawed for quick infusion and do not require extensive tissue-matching have been explored as alternatives to full allogeneic stem cell transplantation following such radiation exposures. Marrow stromal cells (MSCs, also referred to as mesenchymal stem cells) have been proposed as one such cellular therapy to aid regeneration of radiation-induced aplasia; MSCs have shown promise in preclinical studies in rodents and uncontrolled human trials to aid in the regeneration of damaged tissues in experimental models simulating acute graft versus graft disease (aGVHD) [8], renal failure [9], diabetes mellitus [10], and myocardial infarction [11]. However, despite enormous interest in using MSCs to aid in hematopoietic regeneration following radiation exposure, the benefit of MSC infusion on survival after radiation induced marrow damage has only been addressed by a few recent studies [12, 13]. In this study, we sought to determine if a single dose of MSC (either cloned or primary MSC cultures) following lethal dose irradiation would improve survival in the murine model. We also determined the spatial and temporal distribution of infused MSCs in recipients to help better understand the mechanism of action of these cells in improving hematopoietic reconstitution.




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