Subset Of Bone Marrow-derived Cells Research Articles

M2 macrophages promote vasculogenesis during retinal neovascularization by regulating bone marrow-derived cells via SDF-1/VEGF.

Macrophages promote vasculogenesis during retinal neovascularization (RNV) by increasing the recruitment and differentiation of bone marrow-derived cells (BMCs). Different subtypes of macrophages (M1 and M2 macrophages) are associated with RNV. However, the mechanism underlying the regulation of BMCs by different macrophage subtypes during RNV remains unclear. In the present study, we investigated the role and mechanism of action of different macrophage subtypes that regulate BMCs during the development of RNV. The retinal avascular area and neovascularization (NV) tuft area in M2 macrophage group in vivo were the largest compared to those in the control phosphate buffer saline (PBS), unpolarized-M0, and M1 macrophage groups. The number of recruited green fluorescent protein (GFP)-positive BMCs and the degree of differentiation of BMCs into CD31-positive endothelial cells (ECs) and alpha-smooth muscle actin (α-SMA)-positive smooth muscle cells (SMCs) were higher in the M2 macrophage group than in the other groups. M2-conditional medium (M2-CM) affected the in vitro migration and activation of bone marrow mesenchymal stem cells (BMSCs, a subset of BMCs) more than M1-CM. The expression of stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) in M2 macrophages and BMSCs cultured with M2-CM was also higher than that in M1 macrophages and BMSCs cultured with M1-CM. Migration of BMSCs was reduced after inhibiting the SDF-1 signaling pathway. Our results indicate that M2 macrophages may express significantly higher levels of SDF-1 and VEGF than M1 macrophages, thus regulating the recruitment and differentiation of BMCs and further aggravating vasculogenesis during RNV.

An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer.

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13(+) bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b(+)CD13(+) myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b(+)CD13(+) myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs.

Abstract 5202: Bone marrow-derived epithelial cells contribute to chronic skin inflammation and skin tumor formation in the mouse

Abstract Although a stem cell origin for tumors was postulated nearly 200 years ago, a critical role of keratin-15 expressing hair follicle stem cells in skin tumorigenesis has only recently been established. In addition to tissue stem cells, bone marrow cells can play a reparative function in damaged organs and contribute to cancer development as recently demonstrated in a gastric cancer model of Helicobacter felis-induced chronic inflammation. We report here that bone marrow derived cells (BMDCs) are an exogenous source of epithelial cells in tumor development in the multistage skin carcinogenesis model following gender mismatched allogeneic bone marrow transplantation. First, clusters of BMDCs were detected in the epithelium of 37.78% papilloma samples with a genetic marker (EGFP) indicating their bone marrow donor origin. Second, clusters of keratin immunoreactive BMDCs were located primarily in the basal epithelium of the papillomas. Third, a subset of BMDCs in the basal epithelium was found to be highly proliferative as measured by incorporation of BrdU and expression of Ki67. Furthermore, a significant contribution of BMDCs was identified in 53.06% of ulcer-associated dysplastic skin samples by immunostaining and confirmed by presence of a Y chromosome. Moreover, an enhanced contribution of bone marrow-derived epithelial cells was observed in the dysplastic epidermis. Therefore, these results demonstrate that a subset of BMDCs participates as a new epithelial cell source in chronically damaged skin lesions including papillomas and ulcers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5202. doi:1538-7445.AM2012-5202

Bone Marrow Cell Therapies for Endothelial Repair and Their Relevance to Kidney Disease

Endothelial injury is a characteristic finding in chronic kidney disease and is associated with both markedly increased cardiovascular risk and chronic kidney disease progression. The past decade has seen a remarkable surge of interest in the role of bone marrow-derived cells for the protection, repair, and regeneration of injured endothelium. In particular, despite controversies regarding their mechanisms of action, endothelial progenitor cells have garnered considerable attention, with multiple reports suggesting that these cells exhibit remarkable pro-angiogenic effects. Recent advances in our understanding of how the bone marrow responds to endothelial injury now suggest that multiple bone marrow cell populations, including both endothelial progenitor cells and a novel group of cells called early outgrowth cells, promote endothelial repair and regeneration through different, yet complementary, mechanisms. Moreover, certain subsets of bone marrow-derived cells also appear to have novel, potent, angiogenesis-independent tissue-protective properties. The bone marrow should thus now be viewed not only as a hematopoiesis organ, but also as a rich reservoir of cells capable of protecting and even regenerating nonhematopoietic tissues such as the kidney. To harness the prognostic and therapeutic potential of the bone marrow, the renal community must be aware of recent advances in our understanding of the nature and therapeutic potential of these cells.

Bone marrow‐derived proangiogenic cells in pancreatic cancer

Tumor-derived signals systemically induce an angiogenic switch that allows cancer cells to survive and grow. However, the vascular network in tumors is not well organized and fails to meet metabolic needs to maintain tissue homeostasis, resulting in significant hypoxia. Among various tumors, pancreatic ductal adenocarcinoma (PDAC) typically develops in an unusually disordered microenvironment, which contributes to its highly aggressive behavior. Since anti-vascular endothelial growth factor (VEGF) (Avastin) has failed to demonstrate a survival benefit in PDAC, we need to re-visit the basic biology of this disease and understand what makes it so refractory to the anti-angiogenic approaches that are clinically effective in other neoplasms. To address this issue, we specifically focused on the process of neovascularization where bone marrow-derived cells (BMDCs) play a role during pancreatic tumorigenesis. We have identified subsets of BMDCs that regulate key processes during development of the neovessels through paracrine Hedgehog signaling. Considering the importance of systemic responses occurring in tumor bearing hosts, we are currently using genetically engineered mice, which spontaneously develop PDAC, Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) strain, to clarify critical events that can trigger aberrant angiogenesis in pancreatic cancer. These studies allow us to provide insights into the cellular and molecular mechanisms of pancreatic tumorigenesis and have an implication for the design of therapies against this difficult disease.

Abstract 1955: Bone-marrow-derived cells incorporate into the prostate during regrowth

Abstract It is necessary to understand mechanisms of castrate resistant prostate cancer development and progression. As prostate cancer transitions from androgen dependent to castrate resistant, subsequent recurrence involves increased growth of the cancer epithelial cells. Understanding prostate regrowth in a normal prostate will allow us to better understand growth in castrate resistant prostate cancer. We hypothesized that altered chemokine signaling which accompanies the loss and subsequent return of androgen signaling results in the recruitment of immune cells to the prostate microenvironment from the bone marrow. A chimeric mouse model with GFP-labeled bone marrow was used to allow us to identify bone marrow cells recruited to the prostate. We studied how bone marrow derived cells (BMDCs) contributed to an androgen refractory response, specifically prostate regrowth. In a similar mouse model we used GFP-labeled mesenchymal stem cells (MSCs) to study this specific subset of BMDCs in response to prostate regrowth. Host mice were castrated or left intact as a control. Testosterone was given to the chimeric mice. The intact and castrated control mice had a low number of BMDCs recruited to the prostate. However, three and seven days following exogenous testosterone administration resulted in a dramatic increase in BMDC recruitment during prostate regrowth. GFP labeled MSC cells were also recruited to the prostate at three days following treatment with exogenous testosterone. Interestingly, even after four weeks the fully regrown prostates retained BMDCs that appeared to be incorporated in the epithelial compartment. Double immunofluorescence staining showed that a subset of BMDCs gained the expression of androgen receptor; p63, a basal epithelial marker; and cytokeratin 8, a luminal epithelial marker, in the prostate. Rosa26 expressing MSCs injected into GFP mice showed prostate co-localization of ß-galactosidase and GFP, suggesting that MSCs fused with resident prostate epithelial cells during regrowth. The recruitment and eventual incorporation of BMDCs in the prostate suggests a mechanism for exogenous cells in castration-resistant prostate cancer growth. This result has implications for castrate-resistant prostate cancer growth, as it too may be a result of MSC recruitment, incorporation, and fusion. NIH grants F31 GM079879 (VRP), CA108646 and CA126505 (NAB). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1955.

Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes.

Mouse NK1+ T cells constitute a subset of alpha/beta TCR+ T cells that specialize in the rapid production of cytokines, in particular IL-4, and may promote the differentiation of Th2-type CD4 T cells. Their TCRs, like those of a homologous subset of human T cells, use an invariant TCR alpha chain and were recently shown to be specific for the beta 2-microglobulin-associated, MHC class I-like CD1 molecules, which are encoded outside the MHC. In contrast to mainstream thymocytes, which recognize their positively selecting MHC ligand on thymic epithelial cells, positive selection of NK1+ T cells requires their CD1 ligand to be expressed on bone marrow-derived cells. To investigate the nature of the bone marrow-derived cell involved, chimeric mice were constructed with tissues from normal, SCID, and MHC-deficient mice, so that CD1 could be selectively expressed by different subsets of bone marrow-derived cells in the thymus. CD1 expression was also directly assessed using an anti-CD1 mAb, and a CD1-specific T cell hybridoma. The results suggest that immature (CD4+8+ double-positive) cortical thymocytes are the source of CD1 presentation for positive selection of NK1+ T cells.