Nanotopography – potential relevance in the stem cell niche

2014 ◽  
Vol 2 (11) ◽  
pp. 1574-1594 ◽  
Author(s):  
Lesley-Anne Turner ◽  
Matthew J. Dalby
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Osteogenic Differentiation ◽  
Stem Cell Niche ◽  
Potential Role ◽  
Cell Niche

Nanotopographical cues observed in vivo (such as in the sinusoid and bone) closely resemble nanotopographies that in vitro have been shown to promote niche relevant stem cells behaviours; specifically, retention of multipotency and osteogenic differentiation on ordered and disordered nano-pits respectively. These and other observations highlight a potential role for nano topography in the stem cell niche.

Ectopic Human Mesenchymal Stem Cell-Coated Scaffolds Create An In Vivo Leukemia Niche in NOD/SCID Mice.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 559-559
Author(s):  
Sarah Rivkah Vaiselbuh ◽  
Morris Edelman ◽  
Jeffrey Michael Lipton ◽  
Johnson M. Liu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Scid Mice ◽  
Cxcr4 Antagonist ◽  
Cell Niche

Abstract Abstract 559 Introduction: Different cellular components of the normal hematopoietic niche have been identified. However, the niche for malignant hematopoiesis remains to be elucidated. Recent work of other groups has suggested that hematopoietic stem cells (HSC) within the bone marrow anchor themselves in place by attaching to osteoblasts and/or vascular sinusoid endothelial cells. We have recently identified mesenchymal stem cells (MSC) as niche-maker cells and found a crucial role of the SDF-1/CXCR4 axis in this process. Stromal Derived Factor-1 (SDF-1/CXCL12) regulates stem cell trafficking and the cell cycle via its receptor CXCR4. Methods: Polyurethane scaffolds, coated in vitro with human bone marrow MSC, were implanted subcutaneously in non-irradiated NOD/SCID mice. CD34+ HSC or primary AML cells (from a leukapheresis product) were injected either in situ or retro-orbitally in the mice and analyzed for engraftment. The mice were treated twice per week with in situ injections of SDF-1, AMD3100 (a CXCR4 antagonist) or PBS (control). After 2 to 4 weeks, the scaffolds were processed and evaluated for cell survival in the mesenchymal niche by immunohistochemistry. Results: We created in vitro MSC-coated scaffolds that retained inoculated AML cells in the presence of SDF-1, while AML cells seeded on empty scaffolds were not retained. In vivo in NOD/SCID mice, the MSC-coated scaffolds, in the presence of SDF-1 enabled homing of both in situ injected normal CD34+ HSC and retroorbital- or in situ injected primary human AML cells. The scaffolds were vascularized and showed osteoclasts and adipocytes present, suggestive of an ectopic human bone marrow microenvironment in the murine host. Finally, the SDF-1-treated scaffolds showed proliferation of the MSC stromal layer with multiple adherent AML cells, while in the AMD3100-treated scaffolds the stromal lining was thin and disrupted at several points, leaving AML cells free floating in proximity. The PBS-treated control-scaffold showed a thin single cell MSC stromal layer without disruption, with few AML cells attached. Conclusion: The preliminary data of this functional ectopic human microenvironment in NOD/SCID mice suggest that AMD3100 (a CXCR4 antagonist) can disrupt the stem cell niche by modulation of the mesenchymal stromal. Further studies are needed to define the role of mesenchymal stem cells in maintaining the hematopoietic/leukemic stem cell niche in vivo. In Vivo Leukemia Stem Cell Niche: (A) Empty polyurethane scaffold. (B)Vascularization in SQ implanted MSC-coated scaffold (s) niche in NOD/SCID mice. (C) DAB Peroxidase (brown) human CD45 positive nests of AML cells (arrows) 1 week after direct in situ AML injection. (D) Human CD45 positive myeloid cells adhere to MSC in vivo (arrows). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Intestinal Stem Cell Niche Insights Gathered from Both In Vivo and Novel In Vitro Models

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Nikolce Gjorevski ◽  
Paloma Ordóñez-Morán
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Cell Function ◽  
Complex Structure ◽  
Intestinal Stem Cell ◽  
Intestinal Damage ◽  
Cell Niche

Intestinal stem cells are located at the base of the crypts and are surrounded by a complex structure called niche. This environment is composed mainly of epithelial cells and stroma which provides signals that govern cell maintenance, proliferation, and differentiation. Understanding how the niche regulates stem cell fate by controlling developmental signaling pathways will help us to define how stem cells choose between self-renewal and differentiation and how they maintain their undifferentiated state. Tractable in vitro assay systems, which reflect the complexity of the in vivo situation but provide higher level of control, would likely be crucial in identifying new players and mechanisms controlling stem cell function. Knowledge of the intestinal stem cell niche gathered from both in vivo and novel in vitro models may help us improve therapies for tumorigenesis and intestinal damage and make autologous intestinal transplants a feasible clinical practice.

scholarly journals Phage-Based Artificial Niche: The Recent Progress and Future Opportunities in Stem Cell Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Kshitiz Raj Shrestha ◽  
So Young Yoo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Therapeutic Strategy ◽  
Different Types ◽  
Effective Performance ◽  
Cell Niche ◽  
Stem Cell Niches

Self-renewal and differentiation of stem cells can be the best option for treating intractable diseases in regenerative medicine, and they occur when these cells reside in a special microenvironment, called the “stem cell niche.” Thus, the niche is crucial for the effective performance of the stem cells in bothin vivoandin vitrosince the niche provides its functional cues by interacting with stem cells chemically, physically, or topologically. This review provides a perspective on the different types of artificial niches including engineered phage and how they could be used to recapitulate or manipulate stem cell niches. Phage-based artificial niche engineering as a promising therapeutic strategy for repair and regeneration of tissues is also discussed.

MESENCHYMAL TNFR1 EXPRESSION PRESERVES THE COLONIC EPITHELIAL STEM CELL NICHE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S7-S8
Author(s):  
Safina Gadeock ◽  
Cambrian Liu ◽  
Brent Polk
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Mesenchymal Cells ◽  
Epithelial Stem Cells ◽  
Epithelial Stem Cell ◽  
Long Term Treatment ◽  
Lgr5 Expression ◽  
Cell Niche

Abstract Tumor necrosis factor (TNF) is a highly expressed cytokine in inflammatory bowel disease (IBD). Although TNF can induce colonic epithelial dysfunction and apoptosis, recent studies suggest that TNF signalling promotes epithelial wound repair and stem cell function. Here we investigated the role of TNF receptor 1 (TNFR1) in mediating TNF’s effects on colonic epithelial stem cells, integral to mucosal healing in colitis. We demonstrate that Tnfr1-/- mice exhibit loss in Lgr5 expression (-52%, p<0.02; N=6) compared to wildtype (WT) controls. However, the opposite result was found in vitro, wherein murine Tnfr1-/- colonoids demonstrated a significant increase in Lgr5 expression (66%, p<0.007; N=6) compared to WT colonoids. Similarly, human colonoids treated with an anti-TNFR1 antibody also demonstrated an increase in Lgr5 expression, relative to IgG controls. To resolve the contradiction in the in vivo versus in vitro environment, we hypothesized that mesenchymal TNFR1 expression regulates the epithelial stem cell niche. To determine the relationships between these cell types, we co-cultured WT or Tnfr1-/- colonoids with WT or Tnfr1-/- colonic myofibroblasts (CMFs). We found that epithelial Lgr5 expression was significantly higher (by 52%, p<0.05; N=3) when co-cultured with WT compared to TNFR1-/- myofibroblasts. The loss of TNFR1 expression in vivo increases the number of αSMA+ mesenchymal cells by nearly 56% (N=6) but considerably reduces the pericryptal PDGFRα+ cells, suggesting modifications in mesenchymal populations that contribute to the epithelial stem cell niche. Functionally, primary Tnfr1-/--CMFs displayed PI3k (p<0.001; N=3) and MAPK (p<0.01; N=3)-dependent increases in migration, proliferation, and differentiation, but RNA profiling demonstrated by diminished levels of stem cell niche factors, Rspo3 (-80%, p<0.0001; N=6) and Wnt2b (-63%, p<0.008; N=6) compared to WT-CMFs. Supplementation with 50ng recombinant Rspo3 for 5 d to Lgr5-GFP organoids co-cultured with TNFR1-/--CMFs restored Lgr5 expression to wildtype levels. Therefore, TNFR1-mediated TNF signalling in mesenchymal cells promotes their ability to support an epithelial stem cell niche. These results should motivate future studies of the stem cell niche in the context of long-term treatment with anti-TNF therapies.

scholarly journals Renal capsule as a stem cell niche

2010 ◽  
Vol 298 (5) ◽  
pp. F1254-F1262 ◽  
Author(s):  
Hyeong-Cheon Park ◽  
Kaoru Yasuda ◽  
Mei-Chuan Kuo ◽  
Jie Ni ◽  
Brian Ratliff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Cultured Cells ◽  
Renal Parenchyma ◽  
Renal Tubules ◽  
Stem Cell Markers ◽  
Renal Capsule ◽  
Cell Niche

Renal resident stem cells were previously reported within the renal tubules and papillary area. The aim of the present study was to determine whether renal capsules harbor stem cells and whether this pool can be recruited to the renal parenchyma after ischemic injury. We demonstrated the presence of label-retaining cells throughout the renal capsule, at a density of ∼10 cells/mm2, and their close apposition to the blood vessels. By flow cytometry, in vitro cultured cells derived from the renal capsule were positive for mesenchymal stem cell (MSC) markers (CD29+, vimentin+, Sca-1+, nestin+) but did not express hematopoietic and endothelial stem cell markers. Moreover, renal capsule-derived cells also exhibited self-renewal, clonogenicity, and multipotency in differentiation conditions, all favoring stem cell characteristics and identifying them with MSC. In situ labeling of renal capsules with CM-DiI CellTracker demonstrated in vivo a directed migration of CM-DiI-labeled cells to the ischemic renal parenchyma, with the rate of migration averaging 30 μm/h. Decapsulation of the kidneys during ischemia resulted in a modest, but statistically significant, deceleration of recovery of plasma creatinine compared with ischemic kidneys with intact renal capsule. Comparison of these conditions allows the conclusion that renal capsular cells may contribute ∼25–30% of the recovery from ischemia. In conclusion, the data suggest that the renal capsule may function as a novel stem cell niche harboring MSC capable of participating in the repair of renal injury.

scholarly journals Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Theodora Mourtzi ◽  
Dimitrios Dimitrakopoulos ◽  
Dimitrios Kakogiannis ◽  
Charalampos Salodimitris ◽  
Konstantinos Botsakis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Substantia Nigra ◽  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Stem Cell Niche ◽  
Substantia Nigra Pars Compacta ◽  
Dopaminergic Cell ◽  
Cell Niche

Abstract Background Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson’s disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the “weaver” mouse model of PD. Here, we assessed its potential effects on neurogenesis. Methods We quantified total numbers of dopaminergic neurons in the SNpc of wild-type and “weaver” mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20. Results Our analysis revealed the existence of a low-rate turnover of dopaminergic neurons in the normal SNpc and showed, using three independent lines of experiments (stereologic cell counts, BrdU and DiI tracing), that the administration of BNN-20 leads to increased neurogenesis in the SNpc and to partial reversal of dopaminergic cell loss. The newly born dopaminergic neurons, that are partially originated from the SEZ, follow the typical nigral maturation pathway, expressing the transcription factor FoxA2. Importantly, the pro-cytogenic effects of BNN-20 were very strong in the SNpc, but were absent in other brain areas such as the cortex or the stem cell niche of the hippocampus. Moreover, although the in vitro assays showed that BNN-20 enhances the differentiation of NSCs towards glia and neurons, its in vivo administration stimulated only neurogenesis. Conclusions Our results demonstrate the existence of a neurogenic system in the SNpc that can be manipulated in order to regenerate the depleted dopaminergic cell population in the “weaver” PD mouse model. Microneurotrophin BNN-20 emerges as an excellent candidate for future PD cell replacement therapies, due to its area-specific, pro-neurogenic effects.

Matrix Glycoprotein Osteopontin Is a Stem Cell Niche Constituent That Constrains the Hematopoietic Stem Cell Pool Size.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 664-664 ◽  
Author(s):  
Sebastian Stier ◽  
Yon Ko ◽  
Randolf Forkert ◽  
Christoph Lutz ◽  
Thomas Neuhaus ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Stem Cell Pool

Abstract Stem cells reside in a physical niche where a balance of signals controls their growth, differentiation and death. Niche components have generally been defined in terms of cells and positive effects on stem cell maintenance or expansion. Here we define a role for a matrix glycoprotein that provides a constraining function in the hematopoietic stem cell niche. Osteopontin (OPN) is an abundant glycoprotein in bone that can function as either cytokine or cell adhesion mediator. It is known to be produced by multiple cells types including osteoblasts, cells recently defined to be a regulatory component of the hematopoietic stem cell niche. Using studies combining OPN deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell numbers and function. In OPN deficient mice, increased primitive cell numbers were observed in vivo associated with reduced progenitors and reduced primitive cell apoptotic fraction. To determine whether the effect of OPN deficiency was stroma dependent, we performed in vitro stem cell assays on OPN−/− stroma and observed greater LTC-IC supportive capacity compared with wild type stroma. Furthermore, OPN−/− recipients showed a significantly higher proportion of hematopoietic stem cells after transplantation of OPN+/+ bone marrow in comparison to wild-type recipients, indicating that the OPN null microenvironment was sufficient to increase stem cell number. A reduction in apoptotic fraction was seen in primitive cells in the OPN−/− recipient marrows. A role for OPN in apoptosis was confirmed by exogenous OPN in in-vitro studies. Hypothesizing that OPN may serve as a physiologic constraint on stem cell pool size, we compared OPN−/− with wild type animals following parathyroid hormone activation of the stem cell niche. The expansion of stem cells by PTH was superphysiologic in the absence of OPN. Therefore, OPN is a restricting element of the stem cell niche, limiting the number of stem cells produced by niche activation. Extracellular matrix components such as OPN may serve as modulable, regulatory participants in the stem cell niche.

Evidence for a Metabolic Stem Cell Niche.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4046-4046 ◽  
Author(s):  
Michael Cross ◽  
Rudiger Alt ◽  
Lydia Schnapke-Hille ◽  
Thomas Riemer ◽  
Dietger Niederwieser
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Culture Media ◽  
Self Renewal ◽  
Cell Culture Media ◽  
Hematopoietic Stem ◽  
Cell Niche

Abstract The hematopoietic stem cell niche presents a localised environment supporting the balanced maintenance, self-renewal and occasional expansion of the stem cell pool. These options are widely assumed to be regulated exclusively by signalling from specific combinations of stroma-bound or soluble ligands. However, a consideration of the rare conditions under which absolute numbers of stem cells increase in vivo as well as the selective pressures acting on regenerative systems during evolution has led us to propose a metabolic component to the stem cell niche which serves to limit cumulative damage, to avoid the selection of potentially oncogenic mutations and to tie symmetric division to slow proliferation. This would mean that traditional cell culture media based on “systemic” substrates such as glucose and glutamine may actively prevent the symmetric amplification of high quality stem cells, offering a possible explanation for the limited success in this area to date. To investigate this possibility, we have examined the effects of range of carbon and energy sources on the proliferation and maintenance of stem and progenitor cells. Our strategy is to screen a wide variety of culture conditions using murine FDCPmix cells, which are non-tumorigenic but have an innate tendency to amplify symmetrically in the presence of IL-3, and then to test key observations in human UCB CD133+ cells provided with SCF, TPO and FLT-3L. In both cell systems, we do indeed find an unusually low requirement for the systemic substrates glucose and glutamine normally included as major energy and carbon sources in cell culture media. Reducing glucose reduces the yield of committed cells from CD133+ cultures without affecting the accumulation of CD133+CD34+cKit+ progenitors. When provided with alternative substrates more likely to reflect a “niche” type environment, FDCPmix cells can be maintained for long periods in media containing only the trace levels of glucose or glutamine derived from dialysed serum, and show improved self-renewal under these conditions. We have also found that raising osmolarity reduces glucose dependence and simultaneously favours the maintenance both of self-renewing CFU (FDCPmix culture) and of CAFCweek13 (CD133+ culture). In parallel, the use of NMR and mass spectrometry techniques to profile intracellular metabolites in self-renewing and differentiating FDCPmix cells reveals a shift in the metabolite balance indicating reduced glycolysis in the early cells. Taken together, these results suggest that hematopoietic stem cells do indeed have remarkable metabolic characteristics consistent with adaptation to a metabolically limiting niche environment. It may therefore be necessary to identify niche substrates and to combine these with the relevant signalling environment in vitro in order to effectively increase stem cell numbers for research, stem cell transplantation and tissue engineering applications.

Runx1 Maintains Granulocytic-Monocytic Progenitor Numbers By Negatively Regulating Interactions with the Stem Cell Niche

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2913-2913
Author(s):  
Carol Stocking ◽  
Kira Behrens ◽  
Birte Niebuhr ◽  
Ursula Mueller
Keyword(s):  
Stem Cell ◽  
Dna Binding ◽  
Stem Cell Niche ◽  
Target Genes ◽  
Self Renewal ◽  
Cell Niche ◽  
Progenitor Compartment ◽  
Myeloid Progenitors

Abstract The Runx1 transcription factor is among the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the generation of the RUNX1-RUNX1T1 fusion protein in patients with the translocation (8;21), circa 15% of patients with a normal karyotype harbor missense mutations or frame-shift mutations in the RUNX1 gene, in most cases resulting in either a highly compromised protein lacking DNA-binding activity or a null allele. Recent studies have demonstrated that AML transformation normally occurs at the level of the granulocyte-monocyte-progenitor (GMP), thus we sought to dissect the role of Runx1 at this critical stage of myeloid differentiation by examining the hematopoietic progenitor compartment in conditional Runx1 knockout (KO) mice. Earlier studies have demonstrated increased cell numbers in the stem cell compartment in these mice, but a rigorous assessment of myeloid progenitors has not been performed. Our analysis showed that loss of Runx1 resulted in increased levels of all myeloid progenitors, with a 2.2-fold increase in the absolute GMP numbers. Furthermore, Runx1-deficient GMPs gave rise to 40% more colonies than controls, demonstrating increased self-renewal activity within this population. Notably, in addition to being larger, Runx1-deficient colonies did not exhibit the typical structure of GM colonies, which reflects the differentiation status of the cells composing the colonies. Indeed, retarded or impaired differentiation of Runx1-defcient cells was demonstrated by analysis of cell morphology and cell surface markers, with little or no mature forms observed in colonies cultured for 7 to 10 days. Notably, no significant shift to either the G or M lineages was observed in vitro or in vivo. To identify Runx1 target genes that impact at the level of the GMP, expression analysis of Runx1 wild-type and KO GMPs was performed. In addition, the transcriptome of primary KO GMPs genetically engineered to conditionally re-express RUNX1 in vivo was determined before or after Runx1 induction. A total of 36 reciprocally regulated genes were identified using stringent criteria to assess expression levels and fold-induction. Notably, many of the Runx1 target genes encode adhesion factors important for retaining HSPC in the stem cell niche, and which are normally down-regulated during differentiation. These genes were up-regulated in Runx1-deficient GMPs and down-regulated after Runx1 induction. Genome wide DNA-binding analysis established Runx1 binding to regulatory regions of target genes and furthermore revealed cooperative binding of Runx1 with several other TFs implicated in complex networks regulating self-renewal and differentiation of early hematopoietic progenitors. In vitro adhesion assays confirmed that loss of Runx1 resulted in increased adhesion to hematopoietic stromal cells. In summary, we conclude that Runx1 has at least two critical functions in normal myeloid development. In the early stem cell and progenitor compartment, Runx1 represses genes that mediate adhesion to the stem cell niche, thereby facilitating the differentiation program at the expense of self-renewal. On the other hand, during myeloid maturation, Runx1 augments both G and M developmental programs, presumably by facilitating up-regulation of critical granulocytic and monocytic genes. We predict that this former function is of critical importance during leukemogenesis, in which reduced levels of functional Runx1 increases the number of myeloid progenitors with self-renewal potential, which are critical targets of secondary genetic mutations during the clonal evolution of the leukemic clone. Disclosures No relevant conflicts of interest to declare.

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