Direct Evidence of Mesenchymal Stem Cell Tropism for Tumor and Wounding Microenvironments Using In Vivo Bioluminescent Imaging

Abstract

Multipotent mesenchymal stromal/stem cells (MSC) have shown potential clinical utility. However, previous assessments of MSC behavior in recipients have relied on visual detection in host tissue following sacrifice, failing to monitor in vivo MSC dispersion in a single animal and limiting the number of variables that can be observed concurrently. In this study, we utilized noninvasive, in vivo bioluminescent imaging to determine conditions under which MSC selectively engraft in sites of inflammation. MSC modified to express firefly luciferase (MSC-ffLuc) were injected into healthy mice or mice bearing inflammatory insults, and MSC localization was followed with bioluminescent imaging. Inflammatory insults investigated included cutaneous needle-stick and surgical incision wounds, as well as xenogeneic and syngeneic tumors. We also compared tumor models in which MSC were intraveneously or intraperitoneally delivered. Our results demonstrate hMSC-ffLuc systemically delivered to non-tumor bearing animals initially reside in the lungs, then egress to the liver and spleen and decrease in signal over time. However, hMSC in wounded mice engraft and remain detectable only in injured sites. Similarly, in syngeneic and xenogeneic breast carcinoma-bearing mice, bioluminescent detection of systemically delivered MSC revealed persistent, specific co-localization with sites of tumor development. This pattern of tropism was also observed in an ovarian tumor model in which MSC were IP injected. In this study we have identified conditions under which MSC tropism and selective engraftment in sites of inflammation can be monitored by bioluminescent imaging over time. Importantly, these consistent findings were independent of tumor type, immunocompetence and route of MSC delivery.

TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells

“…7 Tumor-directed migration and incorporation of MSCs have been demonstrated in a number of preclinical studies in vitro using transwell migration assays, and in vivo using animal tumor models. The homing capacity of MSCs has been demonstrated with almost all tested human cancer cell lines, including lung cancer, 8 malignant gliomas, 9--11 Kaposi's sarcomas, 12 breast cancer, 13,14 colon carcinoma, 15 pancreatic cancer, 16,17 melanoma 18 and ovarian cancer. 13 Engineered with tumor-specific anticancer genes, MSCs are capable of producing anticancer agents locally and constantly at the tumor site.…”

“…The homing capacity of MSCs has been demonstrated with almost all tested human cancer cell lines, including lung cancer, 8 malignant gliomas, 9--11 Kaposi's sarcomas, 12 breast cancer, 13,14 colon carcinoma, 15 pancreatic cancer, 16,17 melanoma 18 and ovarian cancer. 13 Engineered with tumor-specific anticancer genes, MSCs are capable of producing anticancer agents locally and constantly at the tumor site. One such anticancer agent comes from the tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL), a member of the TNF super-family.…”

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

“…50 Furthermore, several studies have demonstrated MSC tropism on tumors, and our recent work also proved that MSCs can recruit macrophages and promote tumor growth. 24,51,52 Emerging evidence supports the idea that induction of mutations in stromal cells can promote tumor formation. Genetic mutations in stromal cells have been reported in breast cancer.…”

Les cellules souches mésenchymateuses

“…Il faut cependant nuancer ces observations par le fait que ce tropisme n'est pas forcément toujours spécifique de la tumeur ellemême. En effet, l'équipe du docteur F. Marini a notamment montré que les CSM sont en fait capables de migrer de manière plus générale vers les sites d'inflammation consécutifs soit à une blessure soit au développement d'une tumeur [11]. D'autre part, ces auteurs ont aussi montré que les CSM injectées dans la circulation chez des souris intactes avaient un tropisme naturel pour le poumon, le foie et la rate [11].…”

“…En effet, l'équipe du docteur F. Marini a notamment montré que les CSM sont en fait capables de migrer de manière plus générale vers les sites d'inflammation consécutifs soit à une blessure soit au développement d'une tumeur [11]. D'autre part, ces auteurs ont aussi montré que les CSM injectées dans la circulation chez des souris intactes avaient un tropisme naturel pour le poumon, le foie et la rate [11]. Or, une telle comparaison de souris non manipulées à des souris porteuses de tumeurs a rarement été effectuée dans les études antérieures.…”