Hematopoietic Development from Human Induced Pluripotent Stem Cells

Lengerke, Claudia; Grauer, Matthias; Niebuhr, Nina I.; Riedt, Tamara; Kanz, Lothar; Park, In‐Hyun; Daley, George Q.

doi:10.1111/j.1749-6632.2009.04606.x

Cited by 104 publications

(72 citation statements)

References 34 publications

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“…Induced pluripotent stem cells (iPSCs) are pluripotent cells derived from terminally differentiated cells by dedifferentiation. The generation of iPSCs creates the possibility of generating tissue-specific cells, including HSCs [63][64][65][66][67][68] or MSCs [69][70][71][72][73][74][75][76], but further study is required before clinical application of iPSCs can commence. Taken together, immune reconstruction and modification of genetic predisposition of hematopoietic stem cells are important for radical cure of IBD.…”

Section: Intestinal Stem Cells and Other Stem Cells In Ibdmentioning

confidence: 99%

Stem cell therapy for inflammatory bowel disease

2015

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Inflammatory bowel disease (IBD) could be curable by ''immune rest'' and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated ''drugstore'' is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state.Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.

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Section: Intestinal Stem Cells and Other Stem Cells In Ibdmentioning

confidence: 99%

Stem cell therapy for inflammatory bowel disease

2015

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“…In other studies, overexpression of Cdx4 in murine embryonic stem cells facilitated embryoid body and hematopoietic progenitor development and was associated with increased ABD HOX expression (27). Embryoid bodies engineered to co-overexpress Cdx4 and HoxB4 provided complete long term hematopoiesis in lethally irradiated mice, although neither protein had this function alone (28). Additionally, increased Cdx4 expression was documented in bone marrow cells from human subjects with AML (26).…”

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confidence: 93%

HoxA10 Activates CDX4 Transcription and Cdx4 Activates HOXA10 Transcription in Myeloid Cells

Bei

Huang

Wang

et al. 2011

Journal of Biological Chemistry

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HoxA10 is a homeodomain transcription factor that influences a number of developmental processes, including hematopoiesis. During definitive hematopoiesis, expression of HoxA10 is maximal in committed myeloid progenitor cells and decreases as differentiation proceeds. Aberrantly increased expression of HoxA10 was found in bone marrow cells in a poor prognosis subset of human acute myeloid leukemia (AML). Consistent with this, AML developed in mice transplanted with HoxA10-overexpressing bone marrow. However, relatively few target genes have been identified that explain the role of HoxA10 in leukemogenesis. In the current study, we identified CDX4 as a HoxA10 target gene. Cdx4 is a homeodomain transcription factor that was also implicated in myeloid leukemogenesis. Although relatively few Cdx4 target genes have been identified, Cdx4 was known to influence HOX gene transcription. We identified a HoxA10-binding cis element in the CDX4 promoter that activated transcription. We also identified a Cdx4-binding cis element that activated the HOXA10 promoter. Therefore, increased Cdx4 expression in HoxA10-overexpressing cells augmented transcription of the endogenous HOXA10 gene. Increased endogenous HoxA10 in these cells induced additional CDX4 transcription. We found that Cdx4 influenced transcription of HoxA10 target genes in a HoxA10-dependent manner. Similarly, HoxA10 influenced transcription of HOX genes in a Cdx4-dependent manner. We previously found that HoxA10-overexpressing myeloid progenitors were hypersensitive to a variety of cytokines. In the current studies, we found that Cdx4 knockdown decreased cytokine hypersensitivity of HoxA10-overexpressing cells. Therefore, these studies identified a positive feedback relationship between HoxA10 and Cdx4, which potentially amplified the contribution of either transcription factor to the pathogenesis of AML.

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“…1 This year, a brief report in Blood concluded that host IL-17 reduces tumor growth and metastasis. 2 The authors' conclusions relied entirely on one C57BL/6 mouse-derived adenocarcinoma cell line, MC38, in which they showed a 5-fold or greater enhancement in subcutaneous growth and metastases in IL-17-deficient mice compared with control wild-type mice. Their conclusions also contrasted sharply with 3 important previous papers that suggested that IL-17 promoted tumor growth.…”

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confidence: 99%