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Webinar Review: The evolving view of the hematopoietic stem cell niche

Posted By Connections Editor, Wednesday, December 14, 2016

Where are stem cells found and why it matters?

ISEH Webinar review: “The evolving view of the hematopoietic stem cell niche.”

by Kena Flores


It has been almost 40 years since Ray Schofield postulated the existence of a stem cell niche, a specific place within the bone marrow where stem cells reside and interact with “other cell types” that regulate their physiology [1]. Schofield did not know the nature or identity of these cell types, nor the mechanisms by which they regulate the hematopoietic stem cell (HSC) physiology, but he planted the seed of a prolific research field that is now a hot topic on stem cell biology and that is relevant not only for normal hematopoiesis, but for leukemia, stem cell therapy, cell expansion, and aging, among others. To discuss the latest updates on the HSC niche, on 14 June 2016, the new investigator committee organized a webinar titled “The evolving view of the Hematopoietic Stem Cell niche”. The webinar content was didactic and appropriate for the “newbies” in this field, but also for those who have been following this field since its very beginnings. It not only recapitulated where the information about the HSC niche stands now, but it discussed the open questions, and the new directions of this research.


The webinar was moderated by Dr. Cristina Lo Celso, from the Imperial College London, whose research has contributed to the study of the in vivo visualization of the HSC niche. She elegantly introduced both speakers and moderated the Q&A session. The first speaker on the webinar, was Dr. Sean Morrison (Children’s Medical Research Institute, UT Southwestern), who is a researcher that has overcome several technological and conceptual challenges on this field, including defining new HSC markers and developing novel methods to elucidate the nature of the “other cell types” and their mechanisms to regulate HSC physiology. In his talk, Dr. Morrison presented an overall picture of most of his vast contributions, providing a rationale for his research. His approach has not only been to describe the location of HSC, but to elucidate which cells secrete the factors that promote HSC maintenance in the context of the bone marrow anatomy. Dr. Morrison’s group was the first to map the HSC into perivascular areas, a location that has now been validated by other researchers and that it seems to harbor most of the HSC cells.  However, there are multiple cells located into the perivascular areas, including endothelial cells, mesenchymal stromal/stem cells (MSC), and various mesenchymal progenitors and megakaryocytes, so, the nature of the cell types that regulated HSC physiology was still unresolved. To address this issue, Dr. Morrison’s group applied mouse cre technology and deleted three HSC regulators: stem cell factor (Scf), CXCL12 and Angiopoietin 1 (Angpt1) into specific populations, and found that endothelial cells and LepR+ stromal cells are the physiological sources of these HSC factors. Finally, Dr. Morrison presented his most recent papers where he developed a deep imaging and 3D reconstruction of the bone marrow and found that 95% of HSC contact LepR+ perivascular stromal cells, and he finished with the biological characterization of the LepR+ perivascular stromal cells, which are the major source of osteoblasts, adipocytes and cartilage in adult bone marrow.


Dr. Simon Mendez-Ferrer (Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute) provided a brief, but detailed summary of the latest findings on the HSC niche. He stated that “there is more consensus than discrepancies on the field”, a statement that was validated with Dr. Morrison’s presentation, as they both agreed that most HSC reside near blood vessels. It looked like the era of the endosteal niche (that refers to the presence of HSC in endosteal and trabecular areas) has come to an end. It has been only three years since Dr. David Scadden and Dr. Paul Frenette argued about this topic on the second ISEH Webinar.  However, Dr. Mendez-Ferrer raised the fact that endosteal areas are also highly vascular, data that might still leave the “door open” for the endosteal location of HSC within the bone marrow. Dr. Mendez-Ferrer presentation focused on the future challenges, in particular, he analyzed the existence of specific subpopulations of endothelial and perivascular stromal cells that may possess different functional properties, the presence of different niches, and the disadvantages of deleting single molecules from single niche cells that can be technical (inefficient recombination) or biological (redundancy of factors and compensation with other factors). Dr. Mendez-Ferrer finished his presentation with the description of the HSC MSC interactions in myeloproliferative neoplasms, which can be one of the reasons for “why studying the HSC niche matters”.


The webinar closed with a very interesting session of Q&A, in which webinar attendees had the opportunity to have an open dialogue with two of our leaders in this field. Questions about the oxygen levels within the niche, the impact of irradiation and age were addressed by both speakers. One of the topics that raised several questions was the LepR+ stromal cells. Dr. Morrison answered these questions, including questions about the heterogeneity and the possible presence of subpopulations within the LepR+ cells, the use of this marker in humans, and the “exclusivity” of the HSC niche and the fact that there are 100 times more LepR+ stromal cells than HSC.


We received the answers to both of our initial questions at the close of the webinar: HSC are located in perivascular areas and are regulated by endothelial and mesenchymal stromal cells, and it “matters” for many areas, including, normal hematopoiesis, aging, and hematopoietic neoplasms. Nevertheless, and after many years of research, including the research conducted by our two speakers and the moderator, it looks like we are standing at the “tip of the iceberg.”  The HSC niche still has many secrets that need to be elucidated. We are certain that this webinar will inspire you to get involved in this topic, or give you a quick insight/update into this interesting field.


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