Role Of Bone Marrow-derived Progenitor Cells Research Articles

Abstract 566: Role of bone marrow derived cells in response to ionizing radiation in normal brain

Abstract Introduction: Radiation therapy (RTx) plays a critical role in treatment of malignant gliomas however the biological response to ionizing radiation (IR) in normal brain and brain tumors is poorly understood. We postulate that Bone Marrow Derived Progenitor Cells (BMDC) are involved in modulating radiation response in normal brain and brain tumor vasculature. Methods: Animal Models: Bone marrow of NOD/SCID mice were stably reconstituted with BM harvested from green-fluorescent protein transgenic mice. Intracranial (ic) xenografts were generated in intracranial window models (ICW) using U87 glioma cells stably expressing mCherry. RTx: Using locally designed x-ray micro-irradiator stereotactic radiation was delivered through ICW to normal brain or U87-mCherry ic-xenografts, treated with two fractionated regimens of 3×2Gy, 3×5Gy and single radiation doses of 2, 6, 8 and 15 Gy. RTx alone to normal brain was compared to RTx to U87-mCherry ic-xenografts and sham needle injection alone (15 mice each). In-vivo imaging: Two-photon laser capture microscopy was used to obtain high-resolution real-time in-vivo longitudinal images of the tumor cells, tumor vasculature and tracing of the circulating GFP+BM cells. Mice were imaged 1d,2d,3d,7d,10d,14d,21d & 30d following cell implantation or RTx. Histological Analysis: Mice were sacrificed using perfusion fixation and brains collected for correlative immunohistochemical and Immunofluorescent analysis. Results: In normal brain there is a dose dependent recruitment of BMDC to site of IR, in addition to a temporal response.BMDC is seen as early as 12hrs post IR and persists beyond 30 days, which is in contrast to needle injection alone where BMDC dissipate after 7 days. BMDC recruited to sites of IR in normal brain do not migrate outside of the radiation field and do not differentiate into other cell types, which is in striking contrast to glioma intracranial models, where tumor cells trigger a distinct differentiation of BMDC into macrophages, GFAP+astrocytes and monocytes that migrate beyond the irradiated zone. In both normal brain and brain tumor associated vasculature, following IR, BMDC integrates into the vasculature as pericytes and not endothelial cells. At higher radiation doses there is increased BMDC integration into both normal and tumor associated vessels. Conclusions: Our results are the first to demonstrate an early dose dependent recruitment of BMDC to site of IR in normal brain. BMDCs recruited to site of IR require a second signal, such as oncogenic signal from glioma cells, in order to differentiate to form other cell types such as GFAP+astrocytes, Macrophage+ and Monocyte+ cells. Increased integration of BMDC into the vasculature as perictyes following IR is suggestive of a protective role of BMDC. It is conceivable that the recruitment of BMDC to site of radiation in normal brain can be used towards a protective therapeutic strategy against adverse radiation effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 566. doi:10.1158/1538-7445.AM2011-566

515 Role of Bone Marrow-Derived Cells in Experimental Chronic Pancreatitis

Chronic pancreatitis is a known risk factor for pancreatic adenocarcinoma. Recent work has pointed to a role for bone marrow-derived progenitor cells (BMDCs) in chronic inflammation-based carcinogenesis. Consequently, the role of BMDCs in chronic pancreatitis was investigated.The fate of BMDCs was followed using green fluorescent protein and the Y chromosome as bone marrow markers in gender-mismatched transplanted mice treated with repeated injections of cerulein for up to 45 weeks. The phenotype of engrafted BMDCs was assessed based on the co-expression of bone marrow and pancreatic markers.After 45 weeks of cerulein treatment, mice developed severe chronic pancreatitis but no preneoplastic lesions. BMDCs did engraft in the pancreas. Most of the BMDCs were desmin positive and contributed to 5.12% (1.12%) (mean (SEM)) of the pancreatic stellate cell population. Pancreatic stellate cells derived from the bone marrow could be activated, as demonstrated by alpha-smooth muscle actin expression, suggesting a role in tissue repair. BMDCs could also be found in pancreatic ducts, based on dolichos biflorus agglutinin and cytokeratin 19 stainings, but at a much lower frequency (0.62% (0.11%)).BMDCs contribute to the pancreatic stellate cell population, suggesting a role in pancreatic tissue repair. In the absence of preneoplastic lesions, BMDCs contribute at a very low level to the ductal epithelium of the chronically inflamed pancreas. The role of BMDCs in pancreatic carcinogenesis remains to be defined.

Role of bone marrow-derived cells in experimental chronic pancreatitis

Background:Chronic pancreatitis is a known risk factor for pancreatic adenocarcinoma. Recent work has pointed to a role for bone marrow-derived progenitor cells (BMDCs) in chronic inflammation-based carcinogenesis. Consequently, the role...