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• W1994736737 abstract "Discrepancies in published results about the role of N-cadherin in hematopoietic stem cells have led to confusion in the field. Attempting to settle the disagreements and reach a consensus, we undertook a collective discussion approach. This process clarified a number of issues but left some questions still unresolved. Discrepancies in published results about the role of N-cadherin in hematopoietic stem cells have led to confusion in the field. Attempting to settle the disagreements and reach a consensus, we undertook a collective discussion approach. This process clarified a number of issues but left some questions still unresolved. One of the fundamental principles in biology is that cells in multicellular organisms interact and communicate with surrounding cells to acquire or maintain certain properties. This principle is relevant for stem cell biologists as they examine the “niche” hypothesis. The “stem cell niche” concept was first applied to the mammalian hematopoietic stem cell (HSC) field in 1978 (for a review of this area, see Voog and Jones, 2010Voog and JonesCell Stem Cell. 2010; 6: 103-115Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar); however, because of the rarity and low accessibility of HSCs, as well as the lack of specific HSC markers, it has been difficult to examine the specific contact of HSCs with niche cells. Drosophila researchers adopted the niche concept and demonstrated that DE-cadherin and β-catenin interact at the interface between germline stem cells (GSCs) and niche cells. Loss of DE-cadherin leads to the loss of GSCs. These observations in Drosophila gonads encouraged the mammalian HSC field to examine the role of cadherin in the marrow niche. Bone marrow contains a variety of cells that make up stem cell niche. There is evidence suggesting that some cells in the bone marrow express N-cadherin. Three papers published in 2003 and 2004 proposed that bone marrow osteoblasts are HSC niche cells, and two of them additionally showed that osteoblasts and HSCs are positive for immunohistochemical staining with a polyclonal anti-N-cadherin antibody (YS, Japan) (Calvi et al., 2003Calvi L.M. Adams G.B. Weibrecht K.W. Weber J.M. Olson D.P. Knight M.C. Martin R.P. Schipani E. Divieti P. Bringhurst F.R. et al.Nature. 2003; 425: 841-846Crossref PubMed Scopus (2669) Google Scholar, Zhang et al., 2003Zhang J. Niu C. Ye L. Huang H. He X. Tong W.G. Ross J. Haug J. Johnson T. Feng J.Q. et al.Nature. 2003; 425: 836-841Crossref PubMed Scopus (2282) Google Scholar, Arai et al., 2004Arai F. Hirao A. Ohmura M. Sato H. Matsuoka S. Takubo K. Ito K. Koh G.Y. Suda T. Cell. 2004; 118: 149-161Abstract Full Text Full Text PDF PubMed Scopus (1451) Google Scholar). However, none of the studies identified a functional role for N-cadherin in the HSC niche. Wilson et al., 2004Wilson A. Murphy M.J. Oskarsson T. Kalouis K. Bettess M.D. Oser G.M. Pasche A.C. Knabenhans C. MacDonald H.R. Trumpp A. Genes Dev. 2004; 18: 2747-2763Crossref PubMed Scopus (554) Google Scholar found that KLS (c-kit+lineage−Sca-1+) cells are a mixture of N-cadherin-positive and -negative cells based on staining with the YS antibody, but whether those YS antibody-positive cells were long-term repopulating HSCs was unclear. In their model, HSCs lacking c-myc maintain a high level of N-cadherin and other adhesion molecules to enhance stem cell-niche interaction and therefore promote HSC expansion, whereas HSCs with high c-myc repress the adhesion molecules, causing the loss of stem cell-niche interaction and progressive exhaustion of stem cell pool. Later, Hosakawa et al. demonstrated that reactive oxygen species downregulated expression of N-cadherin in LSK-SP (c-kit+lineage−Sca-1+-side population) cells by quantitative RT-PCR and proposed a role of N-cadherin in the HSC-niche interaction (Hosokawa et al., 2007Hosokawa K. Arai F. Yoshihara H. Nakamura Y. Gomei Y. Iwasaki H. Miyamoto K. Shima H. Ito K. Suda T. Biochem. Biophys. Res. Commun. 2007; 363: 578-583Crossref PubMed Scopus (92) Google Scholar). Another follow-up study detected N-cadherin expression in Flk2−LSK HSCs by flow cytometry with a monoclonal N-cadherin antibody (MNCD2) that was verified by RT-PCR. This study indicated that the YS polyclonal antibody does not reliably indicate N-cadherin and instead concluded that flow cytometry with MNCD2 can be used to identify distinct subpopulations of HSCs (Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The authors concluded that Flk2−LSK cells that express intermediate levels of N-cadherin (N-cadherinint) are quiescent HSCs that lack significant reconstituting potential upon transplantation into irradiated mice, whereas cells expressing low levels of N-cadherin (N-cadherinlo) are primed/active HSCs with the capacity to reconstitute irradiated mice (Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). However, two other papers reported no evidence of N-cadherin expression in Flk2−LSK cells or a further enriched population, SLAM-LSK HSCs, by a variety of techniques, including antibody staining and RT-PCR (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, Kiel et al., 2007Kiel M.J. Radice G.L. Morrison S.J. Cell Stem Cell. 2007; 1: 204-217Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). In addition, these authors found that N-cadherin conditional knockout mice had no observable phenotype in HSC frequency, hematopoiesis, long-term competitive repopulation, or serial transplantation (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The observations from the different groups were therefore at odds with one another. The discrepancies described above were generating confusion in the published literature and thus in the field. With the aim of resolving the controversy and providing clarification of the issues involved, we embarked on an interactive discussion approach. At our (L.I.Z.) request, the principal investigators from the two groups that have generated the majority of the conflicting published data, Linheng Li and Sean Morrison, participated in a telephone conference in which each investigator presented and discussed pertinent data slides. This meeting also included another investigator, Toshio Suda, who has published work suggesting a positive role for N-cadherin in the bone marrow, and the editor of Cell Stem Cell, Deborah Sweet. This joint discussion was followed by a series of one-on-one phone meetings and two other telephone conferences with L.I.Z. During the discussion, it became clear that the disagreement centered on three major questions: (1) Do HSCs express N-cadherin? (2) Is the MNCD2 monoclonal antibody specific for N-cadherin? (3) Does N-cadherin play a role in HSC maintenance and regulation? Involving the groups who had previously come to differing conclusions in a joint discussion provided an efficient mechanism for critical analysis of key experimental data and honest expression of opinion about the relevant issues. With the available information, some conclusions about the first two issues became clear, and these will be outlined below. However, we were not able to reach an agreement on the third question on the basis of the available data. Upon the senior scientist's suggestion, the Li and Morrison labs agreed to independently perform a limiting dilution competitive transplantation with the exact same experimental conditions and N-cadherin conditional knockout mice, with a view to comparing data and coming to a consensus conclusion. Several emails between the groups outlined in detail the methods, doses of cells, and mechanism of conditional inactivation of N-cadherin. Six months later, we set up a phone call to examine the data from the two laboratories. During our initial discussions, we were able to come to agreement on a number of points relating to detection of N-cadherin expression in bone marrow cells. In previous studies, the expression of N-cadherin in HSCs has been examined at the mRNA level. The Li and Suda groups found that N-cadherin mRNA can be detected in highly enriched populations of stem cells by quantitative RT-PCR (Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, Hosokawa et al., 2007Hosokawa K. Arai F. Yoshihara H. Nakamura Y. Gomei Y. Iwasaki H. Miyamoto K. Shima H. Ito K. Suda T. Biochem. Biophys. Res. Commun. 2007; 363: 578-583Crossref PubMed Scopus (92) Google Scholar, Hosokawa et al., 2010Hosokawa K. Arai F. Yoshihara H. Iwasaki H. Hembree M. Yin T. Nakamura Y. Gomei Y. Takubo K. Shiama H. et al.Cell Stem Cell. 2010; 6 (this issue): 194-198Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), but Morrison and colleagues did not detect any expression by qRT-PCR or by microarray analysis (Kiel et al., 2007Kiel M.J. Radice G.L. Morrison S.J. Cell Stem Cell. 2007; 1: 204-217Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). Indeed, even in the Li and Suda groups' qRT-PCR assays, the expression level in HSCs was found to be very low compared with some non-HSC control populations. Moreover, no microarray analysis by any group has ever reported the enrichment of N-cadherin in HSCs. With very low levels of expression, divergent findings could potentially be explained by differences in experimental methods and assay sensitivities. The overall conclusion from these data is that N-cadherin RNA is either present at very low levels or absent in HSCs. The majority of the protein expression data presented by Haug et al. were obtained using a monoclonal antibody against N-cadherin, MNCD2 (Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Therefore, challenges to the conclusion that HSCs might express varying low levels of N-cadherin on their surface have centered on concerns about the specificity of the MNCD2 reagent. MNCD2 was originally developed by Matsunami and Takeichi in 1995 (Matsunami and Takeichi, 1995Matsunami H. Takeichi M. Dev. Biol. 1995; 172: 466-478Crossref PubMed Scopus (145) Google Scholar), and its specificity for N-cadherin in western blots was demonstrated by Radice et al., who compared wild-type and N-cadherin null mice (Radice et al., 1997Radice G.L. Rayburn H. Matsunami H. Knudsen K.A. Takeichi M. Hynes R.O. Dev. Biol. 1997; 181: 64-78Crossref PubMed Scopus (580) Google Scholar). The Morrison and Li groups also independently confirmed that MNCD2 was specific for N-cadherin by western blotting and immunostaining using neonatal forebrain cells and cell lines in which N-cadherin is abundantly expressed (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). To examine whether N-cadherin is expressed in enriched HSCs, Kiel et al. sorted 105 LSK cells and carried out western blot analysis with MNCD2. They failed to detect any N-cadherin protein despite readily detecting N-cadhrerin in a few thousand forebrain cells (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Thus, the available data suggest that MNCD2 does give a specific signal by Western blot in tissues in which N-cadherin is highly expressed, but Western blotting with MNCD2 has not been able to confirm N-cadherin expression in the LSK cells. These observations provide further support for the idea that N-cadherin is expressed in a very limited hematopoetic cell population and/or at extremely low levels, or may in fact be absent. Using improved Western blotting techniques and a large number of highly purified cells might reveal the answer. The above conclusions about the expression level of N-cadherin in HSCs raise the possibility that signals obtained for MNCD2 with other assays could be the result of nonspecific binding. Use of the MNCD2 antibody for flow cytometry with enriched HSCs has proved problematic. Haug et al. did see a shift in MNCD2 staining with Flk2-LSK cells compared with the control omitting MNCD2, but in their published study they did not compare this staining with isotype controls to assess staining above background or non-specific antibody binding (Haug et al., 2008Haug J.S. He X.C. Grindley J.C. Wunderlich J.P. Gaudenz K. Ross J.T. Paulson A. Wagner K.P. Xie Y. Zhu R. et al.Cell Stem Cell. 2008; 2: 367-379Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Kiel et al., 2007Kiel M.J. Radice G.L. Morrison S.J. Cell Stem Cell. 2007; 1: 204-217Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar were unable to detect any staining of SLAM-LSK or Flk2-LSK HSCs using MNCD2 or other commercially available anti-N-cadherin antibodies. Moreover, both Kiel et al. and Foudi et al. found that MNCD2 strongly stained surface B220+ B cells in the bone marrow, but when these cells were sorted and analyzed by Western blot, no N-cadherin band was evident (Foudi et al., 2009Foudi A. Hochedlinger K. Van Buren D. Schindler J.W. Jaenisch R. Carey V. Hock H. Nat. Biotechnol. 2009; 27: 84-90Crossref PubMed Scopus (381) Google Scholar, Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The Morrison and Hock groups also examined HSCs enriched by multiple combinations of markers, such as SLAM-LSK and Flk2-LSK, and neither group observed any effect of N-cadherin deficiency on the MNCD2 staining of HSCs or other bone marrow cells (Foudi et al., 2009Foudi A. Hochedlinger K. Van Buren D. Schindler J.W. Jaenisch R. Carey V. Hock H. Nat. Biotechnol. 2009; 27: 84-90Crossref PubMed Scopus (381) Google Scholar, Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). To some extent the differences in results could be due to variation in flow cytometry technique between the labs, different subclones of hybridoma used to produce the antibody, or the conditional knockout efficiency. However, the Morrison laboratory tested multiple aliquots of MNCD2 antibody obtained from the Li laboratory as well as directly from the Developmental Studies Hybridoma Bank and confirmed in all of their experiments that N-cadherin deletion was complete or nearly complete by PCR (S.M. unpublished data). Concerns about these technical differences are heightened by the very low level of proposed N-cadherin expression and the non-specific binding of MNCD2 to HSCs/progenitors. There is no indication from any group that HSCs express high levels of N-cadherin, and instead the accumulated data are consistent with a low level of expression, if any at all, that might be limited to a very small subset of HSCs. Although very low levels of proteins can have a function in cell biology, these data currently cannot be used to support an important HSC function of N-cadherin. These conclusions formed the backdrop against which we discussed our viewpoints on functional studies. To address the question of whether N-cadherin is required for HSC maintenance, Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar studied N-cadherin conditional knockout mice, as the germline knockout is embryonic lethal. They did not observe any change of HSCs or hematopoiesis in homeostatic situations up to 5 months after N-cadherin deletion (using Mx-1-Cre). To further challenge the HSCs, they transplanted 106 bone marrow cells from the N-cadherin conditional knockout mice with comparable numbers of competitive bone marrow cells, and did not observe a significant difference in chimerism relative to wild-type donor cells, even in secondary transplantation. From these experiments, they concluded that HSCs “do not depend on N-cadherin to regulate their maintenance.” N-cadherin could potentially still be required during regeneration or the response to certain types of stresses, and testing the N-cadherin knockout animals for their response during various stresses or irradiation could be interesting. However, the Morrison group failed to see any effect of N-cadherin deletion on the recovery of mice in response to 5-fluorouracil treatment (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar), indicating that N-cadherin does not play an important role in at least this stress condition. During the discussion, the transplantation data by Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar were questioned. One potential issue related to the knockout efficiency in the donor mice, and it was suggested that using reporter mice that can indicate the Cre-mediated recombination activity could be helpful. However, with such an approach it is still possible that the recombination efficiency at the reporter locus could be different from the N-cadherin locus, or could vary between cell populations. As an alternative approach, Morrison's group purified the LT-HSC for clonal culture and performed PCR on each individual colony, showing the knockout efficiency was almost 100%. In addition, the donor-derived cells in the recipients' peripheral blood are also N-cad−/−, further confirming the knockout efficiency (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Based on these results, it seems unlikely that the failure to observe a phenotype is due to incomplete knockout. Even though transplantation is considered the gold standard for testing stem cell functionality, the field has not been able to agree on standardized procedures, and there are substantial inter-lab variances in aspects of hematopoietic transplantation protocols such as donor cell numbers and the cut-off for long-term multi-lineage reconstitution. In an attempt to address the controversy in a rigorous way, L.I.Z. suggested that both groups perform a limiting dilution competitive transplantation independently and compare results, and they agreed to do so. The agreed experiment was that 20,000, 60,000 and 200,000 wild-type or N-cad conditional knockout whole bone marrow cells would be transplanted together with 200,000 competitor cells, and the results examined 16 weeks after transplantation. Six months later, however, only the Morrison lab presented data from the agreed experiment (M. Acar, M. Kiel, and S. Morrison, unpublished data). We examined the resulting data with a biostatistician using standard software for calculating the frequency of hematopoietic stem cell engraftment and ANOVA analysis, and found that there was no difference between the wild-type and N-cadherin deficient groups, consistent with the conclusions published previously by Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar. For additional verification, we also showed the entire analysis to an independent investigator in the hematopoietic stem cell field, who also ran the data through statistical software and came to the same conclusion. Complete N-cadherin deletion was confirmed in these experiments by PCR of genomic DNA from donor cells sorted from the reconstituted mice. However, instead of the agreed set of experiments the Li lab independently chose to undertake a different approach involving using a Cre-loxP reporter system to indirectly indicate the recombination/knockout efficiency and transplanting purified reporter positive and reporter negative cells separately. They observed a difference between these two subsets of cells, which they interpreted as indicating a role for N-cadherin in HSCs (L. Li, unpublished data). However, in our view these experiments are not straightforward to interpret and are therefore not informative for resolving the question at hand. Thus, at this point our conclusion is that no substantial HSC phenotype associated with N-cadherin conditional deletion has been observed, suggesting that N-cadherin does not play an essential functional role in HSCs. Although the data available at this point do not indicate an essential role of N-cadherin in HSCs, redundancy in cadherin function in HSCs remains a possibility. Early experiments showed that HSCs do not express E-cadherin (Zhang et al., 2003Zhang J. Niu C. Ye L. Huang H. He X. Tong W.G. Ross J. Haug J. Johnson T. Feng J.Q. et al.Nature. 2003; 425: 836-841Crossref PubMed Scopus (2282) Google Scholar). However, in this issue of Cell Stem Cell Toshio Suda's group show that the N-cadherin mRNA level in LSK cells differs between mouse strains by qRT-PCR (Hosokawa et al., 2010Hosokawa K. Arai F. Yoshihara H. Iwasaki H. Hembree M. Yin T. Nakamura Y. Gomei Y. Takubo K. Shiama H. et al.Cell Stem Cell. 2010; 6 (this issue): 194-198Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). They found that the C57BL/6 strain has significantly higher N-cadherin level than the 129/Sv strain, from which the N-cadherinfl/- mice were originally derived (Kostetskii et al., 2005Kostetskii I. Li J. Xiong Y. Zhou R. Ferrari V.A. Patel V.V. Molkentin J.D. Radice G.L. Circ. Res. 2005; 96: 346-354Crossref PubMed Scopus (245) Google Scholar). In contrast, the 129/Sv strain has higher expression of other cadherins than the C57BL/6 strain. This could indicate that different cadherins are used by different strains. Interestingly, the Suda group found that overexpressing a dominant-negative(DN) N-cadherin inhibits the lodgment and long-term repopulating activities of HSCs, while overexpressing wild-type N-cadherin has the opposite effect (Hosokawa et al., 2010Hosokawa K. Arai F. Yoshihara H. Iwasaki H. Hembree M. Yin T. Nakamura Y. Gomei Y. Takubo K. Shiama H. et al.Cell Stem Cell. 2010; 6 (this issue): 194-198Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Because of the non-specific blocking of cadherin family members by the DN-N-cadherin (Fujimori and Takeichi, 1993Fujimori E. Takeichi M. Mol. Biol. Cell. 1993; 4: 37-47Crossref PubMed Scopus (178) Google Scholar), this result leaves open the possibility that cell adhesion mediated by the redundant cadherin family members might be involved in HSC activities. However, it is worth noting that Kiel et al. were not able to detect N-cadherin mRNA in C57BL HSCs and studied knockout mice that were backcrossed with C57BL/6 for at least six generations, arguing against the idea that strain background is a basis for the discrepancy in results (Kiel et al., 2009Kiel M.J. Acar M. Radice G.L. Morrison S.J. Cell Stem Cell. 2009; 4: 170-179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Thus, although potential strain differences are intriguing, currently it does not appear likely they can provide an explanation for the different conclusions drawn. In summary, therefore, although there are still differences of opinion among the investigators involved in this process regarding the potential for N-cadherin function in HSCs, it is our view that to move the research in the field forward we need to acknowledge the current observations and set a common foundation for the stem cell community. The current observations on the N-cadherin conditional knockout model indicate that the maintenance of adult HSCs does not appear to depend on N-cadherin homophilic interactions. This conclusion does not support or argue against the potential role of osteoblasts or perivascular cells in the HSC niche, and it does not entirely rule out the idea of cadherin-mediated niche-HSC interaction model as cadherin redundancy is still a possibility. However, convincing evidence to support this idea would require demonstration of a clear HSC defect in knockout mice, either alone or in combination with the N-cadherin knockout, using limiting dilution competitive repopulation studies in the mouse. Our conclusion is that until clear cut data along these lines are forthcoming, the field should not base further experiments on the concept that there is a functionally significant cell-autonomous role for N-cadherin in HSCs. •N-cadherin expression in HSCs is either low or undetectable; if N-cadherin is expressed in HSCs it is present at a very low level and/or in a small subset of cells.•The N-cadherin monoclonal antibody, MNCD2, is not specific for N-cadherin expression in the hematopoietic compartment. This antibody should not be used for experiments that require flow-cytometric sorting of HSCs, although it still can be used to detect N-cadherin expression by Western blot or immunostaining in tissues that express high levels of N-cadherin, such as liver.•Currently available data lead to the conclusion that the maintenance of adult HSCs does not depend on a cell-autonomous role of N-cadherin. To argue against this conclusion, future experiments would need to demonstrate that genetic deficiency of another component, such as a different cadherin, causes a substantial HSC phenotype in N-cadherin conditional knockout mice. Cadherin-Based Adhesion Is a Potential Target for Niche Manipulation to Protect Hematopoietic Stem Cells in Adult Bone MarrowHosokawa et al.Cell Stem CellMarch 05, 2010In BriefDuring postnatal life, hematopoietic stem cells (HSCs) are maintained in specialized bone marrow (BM) niches (Morrison and Spradling, 2008; Wilson and Trumpp, 2006; Yin and Li, 2006). Cadherins are major cell adhesion molecules responsible for Ca2+-dependent cell-cell interaction (Gumbiner, 1996), but the role of cadherin function, and more specifically N-cadherin, in HSC-niche interactions has been controversial (Li and Zon, 2010). In this study, we analyzed the expression of various cadherin (cad) genes in long-term HSCs (LT-HSCs) and subpopulations of the cells isolated from the endosteum. Full-Text PDF Open Archive" @default.
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• W1994736737 title "Resolving the Controversy about N-Cadherin and Hematopoietic Stem Cells" @default.
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