Feto-maternal cell trafficking

The embryonic and fetal development in the maternal uterine environment implies that different population of fetal progenitors must be in close contact to the maternal tissues. Accordingly, fetal mesenchymal and hematopoietic stem and progenitor cells have been described in the placenta and the fetal blood. Seeding in the materinal circulation, fetal progenitor cells can be detected in the circulation of pregnant women during most pregnancies. Decades after delivery, fetal CD34⁺ or mesenchymal stem cells are still detectable in maternal circulation or bone marrow. Recent studies point to the possibility for fetal progenitor cells persisting after pregnancy to home to maternal injured tissue and to adopt various phenotypes. Fetal cells in various maternal tissues can express epithelial, hepatocytic, hematopoietic, renal, cardiomyocytic, glial, or neuronal markers in human as well as mouse models. This apparent multipotency has been attributed to a fetal population of stem/progenitor cells acquired by the mother during pregnancy, named the pregnancy-associated progenitor cells. We will discuss the possible origins of this cell population and review the most recent data suggesting that these fetal microchimeric cells may participate in maternal tissue regeneration processes. An erratum to this article is available at .     

Hematopoietic stem and progenitor cell trafficking

Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients.     

Inhibition of progenitor dendritic cell maturation by plasma from patients with peripartum cardiomyopathy: role in pregnancy-associated heart disease

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF-beta were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM.     

Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle

Trafficking of transplanted endothelial progenitor cells (EPCs) to ischemic tissue is enhanced by stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF). However, it has not been studied how these cytokines modulate the local milieu to entrap EPCs. This study was performed to elucidate a molecular pathway of trafficking EPCs through Akt and to test its application as an adjuvant modality to increase EPC homing. In a mouse hind limb ischemia model, systemically administered 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled mouse EPCs showed three stages of homing to ischemic limb: adhesion to endothelial cells (ECs), incorporation to capillary, and transendothelial migration into extravascular space. As an underlying mechanism to control adhesion of EPCs to ECs, we found that Akt was activated in ECs of ischemic muscle by ischemia-induced VEGF and SDF-1. In vitro and in vivo experiments using adenoviral vector for constitutively active or dominant-negative Akt genes showed that activated Akt enhanced intercellular adhesion molecule 1 (ICAM-1) expression on ECs. Akt activation in ECs also enhanced EPC incorporation to ECs and transendothelial migration in vitro experiments. Activated Akt was sufficient for induction of EPC homing even in normal hind limb, where VEGF or SDF-1 was not increased. Finally, local Akt gene transfer to ischemic limb significantly enhanced homing of systemically administered EPCs, new vessel formation, blood flow recovery, and tissue healing. Akt plays a key role in EPC homing to ischemic limb by controlling ICAM-1 and transendothelial migration. Modulation of Akt in the target tissue may be an adjunctive measure to enhance homing of systemically administered stem cells, suggesting a possibility of cell-and-gene hybrid therapy. Disclosure of potential conflicts of interest is found at the end of this article.     

Polyclonal Treg cells modulate T effector cell trafficking

In this study, we have analyzed the in vivo dynamics of the interaction between polyclonal Foxp3(+) Treg cells, effector T (Teff) cells, and DCs in order to further our understanding of the mechanisms of Treg cell-mediated suppression. Cotransfer of polyclonal activated Treg cells into healthy mice attenuated the induction of EAE. Suppression of disease strongly correlated with a reduced number of Teff cells in the spinal cord, but not with Treg cell-mediated inhibition of Th1/Th17 differentiation. Cotransfer of Treg cells with TCR-Tg Teff cells followed by immunization by multiple routes resulted in an enhanced number of Teff cells in the lymph nodes draining the site of immunization without an inhibition of Teff-cell differentiation. Fewer Teff cells could be detected in the blood in the presence of Treg cells and fewer T cells could access a site of antigen exposure in a modified delayed-type hypersensitivity assay. Teff cells recovered from LNs in the presence of Treg cells expressed decreased levels of CXCR4, syndecan, and the sphingosine phosphate receptor, S1P1 (sphingosine 1-phosphate receptor 1). Thus, polyclonal Treg cells influence Teff-cell responses by targeting trafficking pathways, thus allowing immunity to develop in lymphoid organs, but limiting the number of potentially auto-aggressive cells that are allowed to enter the tissues.     

A two-signal model for T cell trafficking

T-cell-receptor triggering and the delivery of co-stimulation are essential events leading to T cell expansion, differentiation and effector function. The influence that such signals exert on T cell migration during and following priming has been highlighted by recent reports. Moreover, induction of peripheral tolerance might act in part by affecting T cell migration. Here, we propose that the integration of co-stimulatory signals, which regulate the ability of primed T cells to access nonlymphoid tissue, and cognate recognition of the endothelium, which determines the selective recruitment of specific T cells, contribute to the anatomy of T cell-mediated immunity and tolerance. The implications for therapeutic strategies manipulating these signals are discussed.     

Gene transfer into hematopoietic progenitor cells mediated by an adeno-associated virus vector

We describe here the transduction of murine hematopoietic progenitor cells with the dominant selectable neomycin drug-resistance (Neo) gene using a recombinant adeno-associated virus (AAV) vector. Successful transformation of progenitor cells to drug resistance was determined to be approximately 1.5% by colony formation in the presence of geneticin sulfate (G-418). The value of AAV as an alternative to the retrovirus vector systems is discussed.     

Enrichment of marrow hemopoietic progenitor cells using a blood cell processor

A total of 93 bone marrows (BM) from normal donors and patients were processed using the IBM-COBE 2991 blood cell washer to produce a concentrated buffy coat (BC) for either bone marrow transplantation (BMT) or cryopreservation for subsequent autologous BMT. The reduction in volume was 73.3 +/- 8.5% and nucleated blood cells (NBC) recovery was 87.1 +/- 9.1% of original marrow. Red blood cell (RBC) and platelet (PLT) contamination was reduced 64.5 +/- 10.9% and 41.2 +/- 24.1%, respectively. Clonogenic activity indicated that the NBC fraction was highly enriched in hematopoietic progenitor cells (greater than 100%) as assessed in vitro (CFU-GM). Results were not affected by diagnosis, initial marrow volume or cell count of the BM suspension. We conclude that this is a simple and reproducible method using blood bank, facilities and permits BC preparation from BM without significant loss of hematopoietic progenitor cells.     

Endothelial progenitor cell therapy in atherosclerosis: A double-edged sword?

Atherosclerosis, an inflammatory process that selectively affects arteries, is highly prevalent in human. Thrombo-occlusive complications of atherosclerosis, including stroke and myocardial infarction, are becoming major causes of morbidity and mortality in the industrialized world. Atherosclerosis develops in response to local endothelial injuries. Endothelial dysfunction and cell loss are prominent features in atherosclerosis. Restoring the endothelial lining to normal is critical for slowing or reversing the progression of atherosclerosis. Increasing data suggest that endothelial progenitor cells (EPCs) play a significant role in reendothelialization of the injured blood vessels. This review focuses on the effects of EPC mobilization and transfusion in the condition of atherosclerosis. The aim of the review is to provide an update on the progress in this research field, highlight the role of EPCs in atherosclerosis and discuss the possible mechanisms and potential risks of progenitor cell-based therapy in atherosclerosis.     

Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis

AC133 cells, a subpopulation of CD34+ hematopoietic stem cells, can transform into endothelial cells that may integrate into the neovasculature of tumors or ischemic tissue. Most current imaging modalities do not allow monitoring of early migration and incorporation of endothelial progenitor cells (EPCs) into tumor neovasculature. The goals of this study were to use magnetic resonance imaging (MRI) to track the migration and incorporation of intravenously injected, magnetically labeled EPCs into the blood vessels in a rapidly growing flank tumor model and to determine whether the pattern of EPC incorporation is related to the time of injection or tumor size. MATERIALS AND METHODS: EPCs labeled with ferumoxide-protamine sulfate (FePro) complexes were injected into mice bearing xenografted glioma, and MRI was obtained at different stages of tumor development and size. RESULTS: Migration and incorporation of labeled EPCs into tumor neovasculature were detected as low signal intensity on MRI at the tumor periphery as early as 3 days after EPC administration in preformed tumors. However, low signal intensities were not observed in tumors implanted at the time of EPC administration until tumor size reached 1 cm at 12 to 14 days. Prussian blue staining showed iron-positive cells at the sites corresponding to low signal intensity on MRI. Confocal microscopy showed incorporation into the neovasculature, and immunohistochemistry clearly demonstrated the transformation of the administered EPCs into endothelial cells. CONCLUSION: MRI demonstrated the incorporation of FePro-labeled human CD34+/AC133+ EPCs into the neovasculature of implanted flank tumors.     

A microfabricated scaffold for retinal progenitor cell grafting

Diseases that cause photoreceptor cell degeneration afflict millions of people, yet no restorative treatment exists for these blinding disorders. Replacement of photoreceptors using retinal progenitor cells (RPCs) represents a promising therapy for the treatment of retinal degeneration. Previous studies have demonstrated the ability of polymer scaffolds to increase significantly both the survival and differentiation of RPCs. We report the microfabrication of a poly(glycerol-sebacate) scaffold with superior mechanical properties for the delivery of RPCs to the subretinal space. Using a replica molding technique, a porous poly(glycerol-sebacate) scaffold with a thickness of 45 microm was fabricated. Evaluation of the mechanical properties of this scaffold showed that the Young's modulus is about 5-fold lower and the maximum elongation at failure is about 10-fold higher than the previously reported RPC scaffolds. RPCs strongly adhered to the poly(glycerol-sebacate) scaffold, and endogenous fluorescence nearly doubled over a 2-day period before leveling off after 3 days. Immunohistochemistry revealed that cells grown on the scaffold for 7 days expressed a mixture of immature and mature markers, suggesting a tendency towards differentiation. We conclude that microfabricated poly(glycerol-sebacate) exhibits a number of novel properties for use as a scaffold for RPC delivery.     

新的组织工程种子细胞--内皮祖细胞

内皮祖细胞作为一种在血管领域的干细胞在组织工程中有着广阔的应用前景.内皮祖细胞取材方便,参与新生血管的形成,具有成熟内皮细胞相似的特性.因此,内皮祖细胞可能是组织工程血管、血管植入物再内皮化以及构建组织工程器官血管网络的种子细胞的理想来源.简单介绍了内皮祖细胞的来源、特性以及体外扩增技术,并对其在组织工程中应用的研究进展做一回顾.     

Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells

The role of umbilical cord blood (CB)-derived stem cell therapy in neonatal lung injury remains undetermined. We investigated the capacity of human CB-derived CD34(+) hematopoietic progenitor cells to regenerate injured alveolar epithelium in newborn mice. Double-transgenic mice with doxycycline (Dox)-dependent lung-specific Fas ligand (FasL) overexpression, treated with Dox between embryonal day 15 and postnatal day 3, served as a model of neonatal lung injury. Single-transgenic non-Dox-responsive littermates were controls. CD34(+) cells (1 × 10(5) to 5 × 10(5)) were administered at postnatal day 5 by intranasal inoculation. Engraftment, respiratory epithelial differentiation, proliferation, and cell fusion were studied at 8 weeks after inoculation. Engrafted cells were readily detected in all recipients and showed a higher incidence of surfactant immunoreactivity and proliferative activity in FasL-overexpressing animals compared with non-FasL-injured littermates. Cord blood-derived cells surrounding surfactant-immunoreactive type II-like cells frequently showed a transitional phenotype between type II and type I cells and/or type I cell-specific podoplanin immunoreactivity. Lack of nuclear colocalization of human and murine genomic material suggested the absence of fusion. In conclusion, human CB-derived CD34(+) cells are capable of long-term pulmonary engraftment, replication, clonal expansion, and reconstitution of injured respiratory epithelium by fusion-independent mechanisms. Cord blood-derived surfactant-positive epithelial cells appear to act as progenitors of the distal respiratory unit, analogous to resident type II cells. Graft proliferation and alveolar epithelial differentiation are promoted by lung injury.     

新的组织工程种子细胞——内皮祖细胞

内皮祖细胞作为一种在血管领域的干细胞在组织工程中有着广阔的应用前景。内皮祖细胞取材方便，参与新生血管的形成，具有成熟内皮细胞相似的特性。因此，内皮祖细胞可能是组织工程血管、血管植入物再内皮化以及构建组织工程器官血管网络的种子细胞的理想来源。简单介绍了内皮祖细胞的来源、特性以及体外扩增技术，并对其在组织工程中应用的研究进展做一回顾。     

Keratocyte progenitor cell transplantation: A novel therapeutic strategy for corneal disease

Keratocytes are specialised cells that produce and maintain corneal stromal matrix and play a key role in corneal wound healing. Abnormal functioning of these cells is likely to play a central role in corneal disorders, such as keratoconus, which in many cases leads to corneal blindness if untreated. The genetic basis of keratoconus is poorly understood but it is likely that apoptosis pathways are involved. The current paper proposes a novel hypothesis for the treatment and prevention of corneal blindness in disorders such as keratoconus as an alternative to the gold standard treatment of penetrating or partial thickness keratoplasty.     

Application potential of human fetal stem/progenitor cells in cell therapy

We analyzed the possibility of using fetal stem and progenitor cells for the treatment of various pathologies. A comparative characteristic of stem cells from fetuses and adult donors is presented and advantages of the use of fetal biometerial for biotransplantation are described. The main tissue sources of fetal stem cells are characterized and experimental and clinical data on the use of fetal cells for cytotherapy are presented. __________ Translated from Kletochnye Tehnologii v Biologii i Meditsine, No. 1, pp. 5–13, January, 2007     

Adeno-associated virus-mediated gene transfer in hematopoietic stem/ progenitor cells as a therapeutic tool

Hematopoietic stem cells (HSCs) have unique properties of self-renewal, differentiation and proliferation. HSCs are easily accessible, and can be readily delivered back to patients by autologous transplantation, which renders them as attractive targets for ex vivo gene therapy. The adeno-associated virus (AAV) vectors have to date not been associated with any malignant disease, and have gained attention as a potentially safer alternative to the more commonly used retroviral vectors for HSC gene therapy. Although conflicting data exist with regard to HSC transduction by AAV vectors, in this review, we provide an overview of AAV-mediated HSC gene transfer - obstacles as well strategies to improve the transduction efficiency - and the potential use of AAV vectors for gene therapy of human diseases involving HSCs.