Embryonic coronary vasculogenesis and angiogenesis are regulated by interactions between multiple FGFs and VEGF and are influenced by mesenchymal stem cells.

In embryonic hearts explanted on collagen gels, epicardial cells delaminate and form vascular tubes, thus providing a model for coronary tubulogenesis. Using this model, we show that fibroblast growth factors (FGFs) 1, 2, 4, 8, 9, and 18 contribute to tubulogenesis and that the availability of multiple FGFs provides the optimal tubulogenic response. Moreover, the FGF effects are vascular endothelial growth factor (VEGF) -dependent, while VEGF-induced tubulogenesis requires FGF signaling.

Lin- cells mediate tissue repair by regulating MCP-1/CCL-2.

Exogenous bone marrow-derived cells (BMDCs) are promising therapeutic agents for the treatment of tissue ischemia and traumatic injury. However, until we identify the molecular mechanisms that underlie their actions, there can be no rational basis for the design of therapeutic strategies using BMDCs. The pro-healing effects of BMDCs are apparent very shortly after treatment, which suggests that they may exert their effects by the modulation of acute inflammation.

Diabetes and aging alter bone marrow contributions to tissue maintenance.

Bone marrow-derived cells contribute to repair of injured tissue and to the maintenance of tissue homeostasis, but the extent to which perturbations of systemic homeostasis modulate this contribution is unknown. Accordingly, hematopoietic chimeras were used to determine contributions of bone marrow-derived cells to hepatocytes, skeletal muscle myocytes, and cardiomyocytes in healthy young, healthy old, and young obese diabetic mice. Mice with multiple genomic copies of a non-expressed β-globin/pBR322 sequence served as bone marrow donors.

Biology of bone marrow-derived endothelial cell precursors.

Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype.

Differential healing activities of CD34+ and CD14+ endothelial cell progenitors.

Objective: Peripheral blood contains primitive (stem cell-like) and monocytic-like endothelial cell progenitors. Diabetes apparently converts these primitive progenitors, from a pro-angiogenic to anti-angiogenic phenotype. Monocytic progenitors seem to be less affected by diabetes, but potential pro-angiogenic activities of freshly isolated monocytic progenitors remain unexplored.

Old bone marrow cells inhibit skin wound vascularization.

Local injection of hematopoietic stem cell-enriched cells, including mouse lin- cells, accelerates vascularization in animal injury models, apparently by release of angiogenic factors. Locally injected lin- cells from nondiabetic mice dramatically improve, but those from obese diabetic mice inhibit vascular growth in obese diabetic mouse skin wounds. Because of similarities between diabetes and aging and because autologous bone marrow-derived cells are currently being tested in clinical trials involving older patients, we investigated the effects of old lin- cells on skin wound vascularization in nondiabetic and obese diabetic mice.

Obese diabetic mouse environment differentially affects primitive and monocytic endothelial cell progenitors.

Two classes of adult bone marrow-derived endothelial cell (EC) progenitors have been described, primitive hematopoietic stem cell-related cells and monocytic cells. Both differentiate into ECs and promote vascular growth in vivo but have distinct characteristics. Despite the association of obesity and type 2 diabetes with cardiovascular disease, their effects on primitive EC progenitors (prECPs) have not been examined, and the limited data on monocytic EC progenitors are conflicting.

Adult bone marrow-derived hemangioblasts, endothelial cell progenitors, and EPCs.

Long before their existence was proven, work with blood islands pointed to the existence of hemangioblasts in the embryo, and it was widely accepted that such cells existed. In contrast, though evidence for adult hemangioblasts appeared at least as early as 1932, until quite recently, it was commonly assumed that there were no adult hemangioblasts. Over the past decade, these views have changed, and it is now generally accepted that a subset of bone marrow cells or their progeny can and do function as adult hemangioblasts.

Non-classical mechanisms of heart repair.

Vasculogenesis was long considered to be a mechanism of blood vessel formation limited to the embryo, and not used in adult vascular repair. Similarly, myocardial proliferation was generally thought to cease in the adult. Yet there is an extensive older literature suggesting that blood might be a source of adult angioblasts and somewhat more recent data indicate that cardiomyocytes may proliferate.

Epidermal cells accelerate the restoration of the blood flow in diabetic ischemic limbs.

Epidermal progenitor cells (EpPCs) were long thought to be unipotent, giving rise only to other keratinocytes but recent studies question this assumption. Here, we investigated whether mouse EpPCs can adopt other antigenic and functional phenotypes. To test this, we injected freshly isolated and cultured EpPCs and transient amplifying cells into diabetic and non-diabetic mouse ischemic hindlimb and followed the cells' fate and the recovery of the ischemic limb blood flow over time.

Mechanical, cellular, and molecular factors interact to modulate circulating endothelial cell progenitors.

It appears that there are two classes of human circulating endothelial cell (EC) progenitors, CD34+ and CD34-CD14+ cells. Attention has focused on CD34+ cells, yet CD34-CD14+ monocytic cells are far more abundant and may represent the most common class of circulating EC progenitor. Little is known about molecular or physiological factors that regulate putative CD34-CD14+ EC progenitor function, although factors secreted by other blood and cardiovascular cells to which they are exposed probably affect their behavior.

Hemangioblasts, angioblasts, and adult endothelial cell progenitors.

After decades of speculation, proof of embryonic hemangioblasts finally emerged a few years ago. Surprisingly, at about the same time, evidence for adult hemangioblasts began to appear, and recent single-cell bone marrow transplants have confirmed their existence. Embryonic and adult hemangioblasts appear to share antigenic determinants, including CD34, ACC133, and VEGFR2, although their phenotype may be plastic.

Leprdb diabetic mouse bone marrow cells inhibit skin wound vascularization but promote wound healing.

Bone marrow stem cells participate in tissue repair processes and may have roles in skin wound repair. Diabetes is characterized by delayed and poor wound healing, and type 1 diabetes seems to lead to stem cell dysfunction. Hence, stem cell dysfunction could contribute to poor healing, and stem cell-based therapies may be efficacious in diabetic wounds.

Expression of multiple molecular phenotypes by aggressive melanoma tumor cells: role in vasculogenic mimicry.

Cutaneous melanoma has been increasing at an alarming rate over the past two decades, however, there are no acceptable histopathological markers that classify various stages of melanoma progression. Recently, the molecular analysis of cancer has contributed significantly to our understanding of the cellular and molecular underpinnings of tumor progression. The data summarized in this review describe the molecular signature of aggressive cutaneous melanoma cells as that of multiple phenotypes which may be similar to a pluripotent, embryonic-like phenotype.

Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination.

On the basis of the ability of aggressive melanoma cells to participate in vasculogenic mimicry, particularly their expression of endothelial-associated genes, we examined the plasticity of human metastatic cutaneous melanoma cells with respect to vascular function. Fluorescently labeled metastatic melanoma cells were challenged to an ischemic microenvironment surgically induced in the hind limbs of nude mice. The data reveal the capability of these melanoma cells to express cell-fate determination molecules, normally expressed during embryonic vasculogenesis, and to participate in the neovascularization of circulation-deficient muscle.