Hypoxia-Inducible mir-210 Regulates Normoxic Gene Expression Involved in Tumor Initiation

The tremendous need for bone tissue in numerous clinical situations and the limited availability of suitable bone grafts are driving the development of tissue engineering approaches to bone repair. In order to engineer viable bone grafts, one needs to understand the mechanisms of native bone development and fracture healing, as these processes should ideally guide the selection of optimal conditions for tissue culture and implantation. Engineered bone grafts have been shown to have capacity for osteogenesis, osteoconduction, osteoinduction and osteointegration - functional connection between the host bone and the graft. Cells from various anatomical sources in conjunction with scaffolds and osteogenic factors have been shown to form bone tissue in vitro. The use of bioreactor systems to culture cells on scaffolds before implantation further improved the quality of the resulting bone grafts. Animal studies confirmed the capability of engineered grafts to form bone and integrate with the host tissues. However, the vascularization of bone remains one of the hurdles that need to be overcome if clinically sized, fully viable bone grafts are to be engineered and implanted. We discuss here the biological guidelines for tissue engineering of bone, the bioreactor cultivation of human mesenchymal stem cells on three-dimensional scaffolds, and the need for vascularization and functional integration of bone grafts following implantation.

/pdf/tissue-engineered-bone-grafts-biological-requirements-tissue-3z7bu4yp16.pdf

Tissue engineered bone grafts: biological requirements, tissue culture and clinical relevance.

Increasing evidence supports the cancer stem cell hypothesis, which postulates that cancer stem cells are responsible for tumor initiation, metastasis, and resistance to treatments. Therefore, they are the cells to target to cure a cancer. To study the behavior of cancer stem cells, markers for prospective isolation of cancer stem cells are crucial. Recently, CD133 has been used extensively as a marker for the identification of stem cells from normal and cancerous tissues. Several more recent studies, however, indicate that CD133 are expressed in differentiated epithelial cells in various organs, and CD133-negative cancer cells can also initiate tumors. The findings suggest that CD133 is not restricted to somatic stem cells and cancer stem cells. However, in many cases CD133 may be used in combination with other markers or methods to acquire stem cells. In this review, we summarize findings in CD133 expression in various tissues and critically discuss its applications in stem cell isolation.

CD133 as a marker for cancer stem cells: progresses and concerns.

Bone marrow-derived mesenchymal stem cells (MSCs) have demonstrated potential for regenerative medicine strategies Knowledge of the way these cells respond to their environment in in vitro culture and after implantation in vivo is crucial for successful therapy Oxygen tension plays a pivotal role in both situations In vivo, a hypoxic environment can lead to apoptosis, but hypoxic preconditioning of MSCs and overexpression of prosurvival genes like Akt can reduce hypoxia-induced cell death In cell culture, hypoxia can increase proliferation rates and enhance differentiation along the different mesenchymal lineages Hypoxia also modulates the paracrine activity of MSCs, causing upregulation of various secretable factors, among which are important angiogenic factors such as vascular endothelial growth factor and interleukin-6 (IL6) Finally, hypoxia plays an important role in mobilization and homing of MSCs, primarily by its ability to induce stromal cell-derived factor-1 expression along with its receptor CXCR4 This article reviews the current literature on the effects of hypoxia on MSCs and aims to elucidate its potential role in regenerative medicine strategies

The Role of Hypoxia in Bone Marrow–Derived Mesenchymal Stem Cells: Considerations for Regenerative Medicine Approaches

In the bone marrow, hematopietic and mesenchymal stem cells form a unique niche in which the oxygen tension is low. Hypoxia may have a role in maintaining stem cell fate, self renewal and multipotency. However, whereas most studies addressed the effect of transient in vitro exposure of MSC to hypoxia, permanent culture under hypoxia should reflect the better physiological conditions. Morphologic studies, differentiation and transcriptional profiling experiments were performed on MSC cultured in normoxia (21% O2) versus hypoxia (5% O2) for up to passage 2. Cells at passage 0 and at passage 2 were compared, and those at passage 0 in hypoxia generated fewer and smaller colonies than in normoxia. In parallel, MSC displayed (>4 fold) inhibition of genes involved in DNA metabolism, cell cycle progression and chromosome cohesion whereas transcripts involved in adhesion and metabolism (CD93, ESAM, VWF, PLVAP, ANGPT2, LEP, TCF1) were stimulated. Compared to normoxic cells, hypoxic cells were morphologically undifferentiated and contained less mitochondrias. After this lag phase, cells at passage 2 in hypoxia outgrew the cells cultured in normoxia and displayed an enhanced expression of genes (4-60 fold) involved in extracellular matrix assembly (SMOC2), neural and muscle development (NOG, GPR56, SNTG2, LAMA) and epithelial development (DMKN). This group described herein for the first time was assigned by the Gene Ontology program to "plasticity". The duration of hypoxemia is a critical parameter in the differentiation capacity of MSC. Even in growth promoting conditions, hypoxia enhanced a genetic program that maintained the cells undifferentiated and multipotent. This condition may better reflect the in vivo gene signature of MSC, with potential implications in regenerative medicine.

/pdf/long-term-culture-of-mesenchymal-stem-cells-in-hypoxia-k3x43tupq6.pdf

Long term culture of mesenchymal stem cells in hypoxia promotes a genetic program maintaining their undifferentiated and multipotent status

Umbilical cord blood (UCB) and bone marrow (BM)-derived stem and progenitor cells possess two characteristics required for successful tissue regeneration: extensive proliferative capacity and the ability to differentiate into multiple cell lineages. Within the normal BM and in pathological conditions, areas of hypoxia may have a role in maintaining stem cell fate or determining the fine equilibrium between their proliferation and differentiation. In this study, the transcriptional profiles and proliferation and differentiation potential of UCB CD133(+) cells and BM mesenchymal cells (BMMC) exposed to normoxia and hypoxia were analyzed and compared. Both progenitor cell populations responded to hypoxic stimuli by stabilizing the hypoxia inducible factor (HIF)-1alpha protein. Short exposures to hypoxia increased the clonogenic myeloid capacity of UCB CD133(+) cells and promoted a significant increase in BMMC number. The differentiation potential of UCB CD133(+) clonogenic myeloid cells was unaltered by short exposures to hypoxia. In contrast, the chondrogenic differentiation potential of BMMCs was enhanced by hypoxia, whereas adipogenesis and osteogenesis were unaltered. When their transcriptional profiles were compared, 183 genes in UCB CD133(+) cells and 45 genes in BMMC were differentially regulated by hypoxia. These genes included known hypoxia-responsive targets such as BNIP3, PGK1, ENO2, and VEGFA, and other genes not previously described to be regulated by hypoxia. Several of these genes, namely CDTSPL, CCL20, LSP1, NEDD9, TMEM45A, EDG-1, and EPHA3 were confirmed to be regulated by hypoxia using quantitative reverse transcriptase polymerase chain reaction. These results, therefore, provide a global view of the signaling and regulatory network that controls oxygen sensing in human adult stem/progenitor cells derived from hematopoietic tissues.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2006-0398

Transcriptional Profiling of Human Cord Blood CD133+ and Cultured Bone Marrow Mesenchymal Stem Cells in Response to Hypoxia

Blueprint for the Response of Blood and Bone Marrow-Derived Stem Cells and Their Progeny to Hypoxia

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Transcriptional Profiling of Human Cord Blood CD133+ and Cultured Bone Marrow Mesenchymal Stem Cells in Response to Hypoxia

Blueprint for the Response of Blood and Bone Marrow-Derived Stem Cells and Their Progeny to Hypoxia