73 research outputs found
Advances in the management of α-thalassemia major: reasons to be optimistic.
α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition
Thoracoamniotic shunt placement for a right-sided congenital diaphragmatic hernia complicated by hydrops
AbstractMortality associated with congenital diaphragmatic hernia (CDH) is high, and the role of prenatal management continues to evolve. We report a case of a right-sided CDH complicated by fetal hydrops successfully managed with thoracoamniotic shunt placement. Subsequent ultrasounds indicated resolution of hydrops. Despite preterm premature rupture of membrane and preterm delivery at 32 3/7 weeks gestation, the infant survived to hospital discharge at 2.5 months of life. This is the first case of a hydropic right-sided CDH successfully treated with a thoracoamniotic shunt
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Large Differences in Small RNA Composition Between Human Biofluids.
Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for >10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers
Pancreatic Mesenchyme Regulates Epithelial Organogenesis throughout Development
The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator of this process. These results have implications for developing strategies to expand pancreas progenitors and β-cells for clinical transplantation
Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells
In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous
genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In
utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been
shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12
The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and
developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT
has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic
uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further
investigations identified multiple barriers to successful engraftment, including lack of space within the
hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of
IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem
cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and
IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells
because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of
human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment,
differentiation, and systemic repopulation after IUHCT
In Utero Hematopoietic Cell Transplantation for Hemoglobinopathies
In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application
Fetal Therapies and Maternal-Fetal Tolerance
The ability to diagnose and treat genetic diseases before birth represents one of the foremost breakthroughs of modern medicine. While fetal surgery has advanced in the last several decades, the prospect of applying developments in stem cell biology and gene therapy to the fetal environment remains an open frontier. This issue represents the work of international experts in the field of fetal therapy, who came together at the first meeting of the International Fetal Transplantation and Immunology Society in 2014. This meeting was convened in an effort to provide a consensus for future applications of in utero transplantation and gene therapy, as well as form an international community of colleagues to nurture this field
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