Abstract
Mesenchymal stromal cells (MSCs) have shown promise as treatment for graft-versus-host disease (GvHD) following allogeneic bone marrow transplantation (alloBMT). Mechanisms mediating in vivo effects of MSCs remain largely unknown, including their biodistribution following infusion. To this end, human bone-marrow derived MSCs (hMSCs) were injected via carotid artery (IA) or tail vein (TV) into allogeneic and syngeneic BMT recipient mice. Following xenogeneic transplantation, MSC biodistribution was measured by bioluminescence imaging (BLI) using hMSCs transduced with a reporter gene system containing luciferase and by scintigraphic imaging using hMSCs labeled with [(99m)Tc]-HMPAO. Although hMSCs initially accumulated in the lungs in both transplant groups, more cells migrated to organs in alloBMT recipient as measured by in vivo BLI and scintigraphy and confirmed by ex vivo BLI imaging, immunohistochemistry and quantitative RT-PCR. IA injection resulted in persistent whole-body hMSC distribution in alloBMT recipients, while hMSCs were rapidly cleared in the syngeneic animals within one week. In contrast, TV-injected hMSCs were mainly seen in the lungs with fewer cells traveling to other organs. Summarily, these results demonstrate the potential use of IA injection to alter hMSC biodistribution in order to more effectively deliver hMSCs to targeted tissues and microenvironments.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) plays a significant role in the treatment of various malignant and nonmalignant diseases, including hematological disorders, metabolic storage disease, immune deficiencies and leukemia
Patterns of human bone marrowderived MSCs (hMSCs) biodistribution differ between types of bone marrow transplantation To study their biodistribution in transplant recipient mice using bioluminescence imaging (BLI), hMSCs were lentiviral-transduced with a triple-fusion, firefly luciferase reporter gene
One million hMSCs were tailvein (TV) injected on days 1 and 4 following bone marrow transplantation (BMT) and daily BLI was performed in animals for up to six weeks post-BMT. hMSCs initially migrated to the pulmonary circuit in both syngeneic and allogeneic BMT mice, but only in allogeneic BMT mice did hMSCs eventually redistribute throughout the animal with greatest BLI signal intensity noted in the gastrointestinal (GI) tract (Figure 1)
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) plays a significant role in the treatment of various malignant and nonmalignant diseases, including hematological disorders, metabolic storage disease, immune deficiencies and leukemia. MSCs from numerous sources, including bone marrow and umbilical cord blood, can be expanded and have minimal infusion-related toxicity and side effects[4]. Given their immunosuppressive and expansion capabilities, MSCs have been used as cellular therapy for GvHD[5]. In this regard, we have recently shown that human bone marrowderived MSCs (hMSCs) injected via tail vein (TV) can attenuate acute GvHD severity while maintaining potent GvL activity following murine allogeneic bone marrow transplantation (BMT)[6]
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