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Biomedical subjects

David Lyden

Publications and source records attributed to David Lyden.

At least 19 recordsLinked to original sources
PubMed2007

Niche-to-niche migration of bone-marrow-derived cells.

During ontogenesis, haematopoietic stem cells (HSCs) relocate between extra-embryonic and embryonic compartments. Similarly, site-specific homing of HSCs is ongoing during adulthood. With the expanding knowledge of HSC physiology, a new paradigm emerges in which HSCs and haematopoietic progenitor cells (HPCs) migrate to defined microenvironments within the bone marrow (BM) and to 'activated' or 'inducible' niches elsewhere. Here, we summarize current understanding of HSC niche characteristics, and the physiological and pathological mechanisms that guide HSC homing both within the BM and to distant niches in the periphery, promoting new vessel growth in tumours and ischaemia. Recent observations suggest that features of the HSC niche might also be recapitulated in pre-metastatic sites. Clusters of BM-derived HPCs promote invasion of disseminating cancer cells. Clear clinical benefits can be foreseen by modulating HSCs and their microenvironments, in promoting tissue regeneration, and inhibiting tumourigenesis and cancer metastasis.

Animals↗
PubMed2006

Preparing the "soil": the premetastatic niche.

Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site. Specific up-regulation of fibronectin and clustering of bone marrow-derived cellular infiltrates coexpressing matrix metalloproteinases in distant tissue sites before tumor cell arrival are proving to be indispensable for the initial stages of metastasis. These bone marrow-derived hematopoietic progenitors that express vascular endothelial growth factor receptor 1 mobilize in response to the unique array of growth factors produced by the primary tumor. Their arrival in distant sites represents early changes in the local microenvironment, termed the "premetastatic niche," which dictate the pattern of metastatic spread. Focus on the early cellular and molecular events in cancer dissemination and selectivity will likely lead to new approaches to detect and prevent metastasis at its earliest inception.

Bone Marrow Cells↗
PubMed2006

Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.

Animals↗
PubMed2006

Bone marrow cells in the 'pre-metastatic niche': within bone and beyond.

Metastasis, the spread of invasive carcinoma to sites distant from the primary tumor, is responsible for the majority of cancer-related deaths (Weigelt, B., Peterse, J. L., & van 't Veer, L. J. (2005). Breast cancer metastasis: Markers and models. Nature Reviews. Cancer, 5, 591-602). Despite progress in other areas of cancer therapeutics, the complexities of this process remain poorly understood. Consequently, there are few successful treatments that directly target this stage of carcinogenesis. Particularly enigmatic is the tissue-specificity of different tumor types observed in metastatic spread. One example is the predilection of colon cancer to spread to liver whereas breast, prostate, and lung carcinomas have a particular affinity to target and proliferate in bone. In 1889, Stephen Paget observed that circulating tumour cells would only "seed" where there was "congenial soil". Since then, attention has focused on explaining the dynamic adhesive and migratory capabilities intrinsic to tumor cells. Meanwhile, the earliest changes occurring within distant tissues that prime the "soil" to receive incoming cancer cells have largely been neglected. Recent work characterizing the importance of bone marrow-derived hematopoietic progenitor cells (HPC) in initiating these early changes has opened new avenues for cancer research and chemotherapeutic targeting (Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438, 820-827). This review discusses the inextricable relationship between bone stromal components, metastasizing cells, and bone marrow-derived hematopoietic cells, and their roles in carcinogenesis and metastasis. Understanding these dynamics may help explain the tissue-specific tropism seen in metastasis. Moreover, exploring the earliest events promoting circulating cancer cells to engraft and establish at secondary sites may expose new targets for diagnostic and therapeutic strategies and reduce the morbidity and mortality from metastatic disease.

Animals↗
PubMed2005

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Animals↗
PubMed2005

p130Rb2 and p27kip1 cooperate to control mobilization of angiogenic progenitors from the bone marrow.

Neoangiogenesis involves both bone marrow-derived myelomonocytic and endothelial progenitor cells as well as endothelial cells coopted from surrounding vessels. Cytokines induce these cells to proliferate, migrate, and exit the cell cycle to establish the vasculature; however, which cell cycle regulators play a role in these processes is largely unknown. Here, we report that mice lacking the cell cycle inhibitors p130 and p27 show defects in tumor neoangiogenesis, both in xenografts and spontaneously arising tumors. This defect is associated with impaired mobilization of endothelial and myelomonocytic angiogenic progenitors from the bone marrow. This article documents the role of these molecules in angiogenesis and further suggests that cell expansion and mobilization from the bone marrow of angiogenic precursors are separable events.

Animals↗
PubMed2005

AC133/CD133/Prominin-1.

Prominin-1, originally found on neuroepithelial stem cells in mice, is a five transmembrane domain cell-surface glycoprotein that localizes to membrane protrusions. Its homologue human Prominin-1 was first isolated from hematopoietic stem cells by a monoclonal antibody recognizing a specific epitope designated as AC133 (CD133). Transcription of Prominin-1 is driven by five tissue-specific alternative promoters resulting in the formation of differentially spliced mRNA isoforms. Prominin-1 is expressed on different types of stem cells, but it is not known if it plays a significant role in key stem cell functional features. Although the biological function of Prominin-1 is not well understood, the AC133 epitope currently serves as a useful marker for the isolation of hematopoietic and endothelial progenitor cells.

AC133 Antigen↗
PubMed2003

Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis.

The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.

Animals↗
PubMed2003

Patterns of failure using a conformal radiation therapy tumor bed boost for medulloblastoma.

PURPOSE: To assess the patterns of failure for patients with medulloblastoma receiving a conformal tumor bed boost rather than a boost to the entire posterior fossa. PATIENTS AND METHODS: From 1994 to 2002, 32 consecutive patients with newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer Center (New York, NY) received a conformal boost to the tumor bed in conjunction with craniospinal radiation therapy. Twenty-eight patients also received chemotherapy. The median age was 9 years (range, 3 to 34 years), and the male to female ratio was 3:1. Twenty-seven patients had standard-risk disease, and five patients had high-risk disease. Craniospinal doses ranged from 23.4 to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy. RESULTS: With a median follow-up of 56 months, six patients have relapsed; five relapsed outside of the posterior fossa, and one failed within the posterior fossa, outside of the high-dose boost volume. Five-year actuarial disease-free and overall survival rates were 84% and 85%, respectively. Freedom from posterior fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from distant failure was 84% at 5 years, with a trend for improvement when full-dose craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose (23.4 Gy) of radiation (100% v 63%, respectively; P =.06). No other predictive variables were identified. CONCLUSION: Conformal treatment to the tumor bed allows for significant sparing of critical structures. The posterior fossa failure rate in this series is similar to that reported when the entire posterior fossa is treated. This approach should be investigated further in a phase III trial.

Adolescent↗
PubMed2003

Tumor response to radiotherapy regulated by endothelial cell apoptosis.

About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

Animals↗
PubMed2003

Primary leptomeningeal primitive neuroectodermal tumor.

Leptomeningeal metastases are a common complication of medulloblastomas and other primitive neuroectodermal tumors (PNETs). Much rarer are PNETs apparently arising in the leptomeninges. An 8-year-old boy presented with headache and vomiting, due to neoplastic meningitis from primary neuroectodermal tumor without an identifying mass. After craniospinal irradiation and chemotherapy (carboplatin, vincristine, cyclophosphamide and lomustine) the boy was in remission for 14 months, then suffered several relapses despite various chemotherapy regimens. After the initial presentation of 3.5 years the boy began to suffer from prolonged refractory non-convulsive status epilepticus and later expired from progression of primary leptomeningeal PNET.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.

Emerging evidence suggests that bone marrow-derived endothelial, hematopoietic stem and progenitor cells contribute to tissue vascularization during both embryonic and postnatal physiological processes. Recent preclinical and pioneering clinical studies have shown that introduction of bone marrow-derived endothelial and hematopoietic progenitors can restore tissue vascularization after ischemic events in limbs, retina and myocardium. Corecruitment of angiocompetent hematopoietic cells delivering specific angiogenic factors facilitates incorporation of endothelial progenitor cells (EPCs) into newly sprouting blood vessels. Identification of cellular mediators and tissue-specific chemokines, which facilitate selective recruitment of bone marrow-derived stem and progenitor cells to specific organs, will open up new avenues of research to accelerate organ vascularization and regeneration. In addition, identification of factors that promote differentiation of the progenitor cells will permit functional incorporation into neo-vessels of specific tissues while diminishing potential toxicity to other organs. In this review, we discuss the clinical potential of vascular progenitor and stem cells to restore long-lasting organ vascularization and function.

Animals↗
PubMed2002

Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment.

The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.

Animals↗
PubMed2002

Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.

Stem cells within the bone marrow (BM) exist in a quiescent state or are instructed to differentiate and mobilize to circulation following specific signals. Matrix metalloproteinase-9 (MMP-9), induced in BM cells, releases soluble Kit-ligand (sKitL), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. BM ablation induces SDF-1, which upregulates MMP-9 expression, and causes shedding of sKitL and recruitment of c-Kit+ stem/progenitors. In MMP-9-/- mice, release of sKitL and HSC motility are impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous sKitL restores hematopoiesis and survival after BM ablation. Release of sKitL by MMP-9 enables BM repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.

Animals↗
PubMed2002

Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function.

Delivery of young bone marrow-derived stem cells offers a novel approach for restoring the impaired senescent cardiac angiogenic function that may underlie the increased morbidity and mortality associated with ischemic heart disease in older individuals. Recently, we reported that alterations in endothelial cells of the aging heart lead to a dysregulation in the cardiac myocyte platelet-derived growth factor (PDGF)-B-induced paracrine pathway, which contributes to impaired cardiac angiogenic function. Based on these results, we hypothesized that cellular restoration of the PDGF pathway by bone marrow-derived endothelial precursor cells (EPCs) could reverse the aging-associated decline in angiogenic activity. In vitro studies revealed that young murine (3-month-old) bone marrow-derived EPCs recapitulated the cardiac myocyte-induced expression of PDGF-B, whereas EPCs from the bone marrow of aging mice (18-month-old) did not express PDGF-B when cultured in the presence of cardiac myocytes. Transplantation of young, but not old, genetically marked syngeneic bone marrow cells into intact, unirradiated aging mice that populated the endogenous senescent murine bone marrow incorporated into the neovasculature of subsequently transplanted syngeneic neonatal myocardium. Moreover, the young bone marrow-derived EPCs restored the senescent host angiogenic PDGF-B induction pathway and cardiac angiogenesis, with graft survival and myocardial activity in the aging murine host (cardiac allograft viability: 3-month-old controls, 8/8; 18-month-old controls, 1/8; 18-month-old donors receiving bone marrow from 3-month-old mice, 15/16; or 18-month-old mice, 0/6; P<0.05). These results may offer a foundation for the development of novel therapies for the prevention and treatment of cardiovascular disease associated with aging.

Aging↗
PubMed2002

Contribution of marrow-derived progenitors to vascular and cardiac regeneration.

Adult bone marrow is a rich reservoir of tissue-specific pluripotent stem and progenitor cells. Accumulating evidence suggest that these cells have the potential of contributing to tissue revascularization and cardiac regeneration. Physiological stress results in the release of specific chemokines and cytokines that promote mobilization of stem cells to the peripheral circulation. Incorporation of these mobilized cells contributes to formation of functional vasculature and sets up stage for tissue regeneration. Vascular Endothelial Growth Factor (VEGF) through interaction with its receptors VEGFR2 and VEGFR1 expressed on endothelial and hematopoietic stem cells promote recruitment of these cells into the sites of tissue injury accelerating vascular healing. Similarly, subset of CD34 + marrow derived cells are mobilized and recruited to the ischemic myocardium, differentiating into cardiac and vascular cells, restoring cardiac function. Identification of cellular mediators and tissue specific chemocytokines that facilitate selective recruitment of marrow-derived stem and progenitor cells to specific organs, will open up new avenues to accelerate cardiovascular regeneration and tissue revascularization.

Animals↗