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The Niche for Hematopoietic Stem Cell Expansion: a Collaboration Network

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The Niche for Hematopoietic Stem Cell Expansion: a Collaboration Network Cellular & Molecular Immunology (2017) 14, 865–867 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi LETTER TO THE EDITOR The niche for hematopoietic stem cell expansion: a collaboration network Qingfeng Chen1,2,3,4 Cellular & Molecular Immunology (2017) 14, 865–867; doi:10.1038/cmi.2017.74; published online 28 August 2017 ransplantation of hematopoietic Despite intensive research over the CD34hiCD133neg phenotype defines Tstem/progenitor cells (HSPC) has past several decades, there has not been hematopoietic progenitor cells and only become one of the most effective treat- a clear overall picture of how the hema- contributes to the differentiation of spe- ments for several hematological malig- topoietic stem cell niche functions in the cificlineages.9 According to another nancies, cancers and genetic immune expansion of primitive and self-renewing study, mesenchymal stem cells engi- disorders. However, the lack of histo- HSPCs. Many studies have shown that neered to express growth factors can compatible donor sources and the num- the expansion of HSPCs depends on robustly support the expansion of ber of stem cells suitable for engraftment some well-known growth factors, such CD34hiCD133hi cells, and both cell-cell are major constraints in the clinic, and as stem cell factors, flt3 ligands, throm- contact and soluble factors are essential these constraints greatly hamper the use bopoietin, interleukin 6, interleukin-3 for this process.10 Yong et al.11 recently of stem cell therapy. In humans, fetal and angiopoietin-like 5, which function identified a novel human liver progenitor 1–3 liver and bone marrow are the two major in different combinations, and newly cell population in the fetal liver with a lo lo locations of hematopoiesis before and recognized factors such as notch ligand unique phenotype of CD34 CD133 . 4,5 after birth, respectively. Thus, under- and stemregenin 1. However, whether This pluripotent cell population could standing the specialized stem cell micro- cytokines alone lead to HSPC expansion give rise to multiple cell lineages, environment supporting the self-renewal with self-renewing capacity remains including hepatocytes, endothelial and expansion of HSPC in fetal liver and unclear, as previous studies have also cells, adipocytes and osteocytes; thus, lo lo bone marrow is not only essential for indicated that direct interactions between CD34 CD133 cells contribute an HSPCs and cellular components, such as essential component in the fetal liver extending the current knowledge of stem lo lo cell biology but is also beneficial to adult blood vessel endothelial cells, osteoblasts, niche. Furthermore, CD34 CD133 cells mesenchymal stem cells and so on, in the express principal growth factors that are regenerative medicine in the clinic. stem cell niche are crucial for the regula- important for stem cell expansion such tion of hematopoiesis.6,7 Moreover, there as stem cell factor, insulin-like growth 1 Institute of Molecular and Cell Biology, Agency are ongoing debates about whether factor 2, C–X–C motif chemokine 12 for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; HSPCs lose long-term grafting ability (CXCL12) and factors in the 2Department of Microbiology and Immunology, during in vitro expansion as a result of angiopoietin-like protein family. The Yong Loo Lin School of Medicine, National Uni- the loss of a proper stem cell-forming co-culture of fetal liver CD34loCD133lo versity of Singapore, Singapore 119228, Singa- hi 3 niche, which has not yet been accurately cells with autologous fetal liver CD34 pore; National Cancer Centre Singapore, Singapore 169610, Singapore and 4Key Labora- formatted in existing stem cell HSPCs or allogenic cord blood HSPCs tory for Major Obstetric Diseases of Guangdong protocols.8 New insights into the hema- supports the ex vivo expansion of HSPCs Province, The Third Affiliated Hospital of Guangz- topoietic stem cell niche are required. from both resources. In addition, this hou Medical University, Guangzhou 510150, China In a previous study, we showed that new co-culture-based expansion only Correspondence: Dr Q Chen, Institute of Mole- human hematopoietic stem cells in the relies on the soluble factors secreted cular and Cell Biology, Proteos, 61 Biopolis Drive, fetal liver, cord blood and bone marrow, from CD34loCD133lo cells and is cell- Singapore 138673, Singapore in vivo E-mail: [email protected] which carry the actual long-term cell contact independent. Received: 28 June 2017; Accepted: 29 June repopulating activity, possess a unique Considering these results, it is thought 2017 phenotype of CD34hiCD133hi,whilethe that there is a network of various cell Hematopoietic stem cell niche QChen 866 Figure 1 Two major types of feeder cells for HSPCs in a fetal liver stem cell niche. types that reconstitute the hematopoietic culture system can be obtained from the immobilized factors? The following strat- stem cell niche in the fetal liver. Some growth factors and the membrane- egy to characterize and simplify the stem groups of stromal cells in stem cell niche bound proteins that are present on cell niche could be explored: first, gently could be responsible for producing feeder cells isolated from fetal livers, disassociate the cellular network in the growth factors to support stem cell respectively. However, it is likely to be fetalliver,followedbyanex vivo 3D lo lo expansion, for example, CD34 CD133 infeasible to continuously culture all co-culture-based screening system and cells, while certain cell types provide cell- potential feeder cell types in a single cell ablation to identify the essential cell ex vivo cell contact with additional stimulating culture system, considering the components under the most robust con- fi signals, for example, mesenchymal stem dif culty in obtaining and maintaining ditions for the expansion of HSPCs. cells; other cell types potentially have the these cells for even a short period of time Proteomics and bioinformatics should two overlapping features (Figure 1). without changing their original features. subsequently be applied to identify the These cells are referred to as stromal Yong demonstrated that over time, pri- principal growth factors secreted and to cells, which contribute soluble and/or mary CD34loCD133lo feeder cells rapidly characterize the membrane-bound membrane-bound signals to HSPCs as change in vitro, leading to a dramatic receptor/ligand patterns formed between ‘feeder cells’, while those that are not decrease in the HSPC expansion effi- feeder cells and HSPCs. Finally, selected involved in stem cell maintenance act as ciency when cultured for more than 7 fi ‘non-feeder cells’. Considering the com- days.11 Thus, a feeder-free system in a combinations should be veri ed in a plexity of the stem cell niche and the 2D or a 3D format is likely to be more novel feeder-free culture system with limited time and extent of stem cell sustainable. In addition, although Yong both soluble and anchored components. expansion that researchers can currently detected the expression of a few key achieve, the existing conditions for growth factors at the mRNA level, their ex vivo CONFLICT OF INTEREST stem cell expansion remain far protein translation, which is the real The author declares no conflict of interest. from optimal. To achieve long-lasting effector, could vary; the few known robust ex vivo stem cell renewal and factors may only represent a small por- expansion, new factors should be tion of the natural cocktail. ACKNOWLEDGEMENTS explored to better mimic the hemato- Can we overcome these issues and QC is supported by the Singapore poietic stem cell niche. Theoretically, customize a feeder-free system with a National Research Foundation Fellowship soluble and fixed components in a co- combination of optimized soluble and (NRF-NRFF2017-03). Cellular & Molecular Immunology Hematopoietic stem cell niche QChen 867 5 Wagner Jr JE, Brunstein CG, Boitano AE, 9 ChenQ,KhouryM,LimmonG,ChoolaniM, 1 Zhang CC, Kaba M, Iizuka S, Huynh H, DeFor TE, McKenna D, Sumstad D et al. Chan JK, Chen J. Human fetal hepatic Lodish HF. Angiopoietin-like 5 and IGFBP2 Phase I/II trial of stemregenin-1 expanded progenitor cells are distinct from, but closely stimulate ex vivo expansion of human cord umbilical cord blood hematopoietic stem related to, hematopoietic stem/ blood hematopoietic stem cells as assayed cells supports testing as a stand- progenitor cells. Stem Cells 2013; 31: alone graft. Cell Stem Cell 2016; 18: 1160–1169. by NOD/SCID transplantation. Blood 2008; – 111:3415–3423. 144 155. 10 Khoury M, Drake A, Chen Q, Dong D, 2 Gammaitoni L, Bruno S, Sanavio F, Gunetti M, 6 Crane GM, Jeffery E, Morrison SJ. Adult Leskov I, Fragoso MF et al. Mesenchymal Kollet O, Cavalloni G et al. Ex vivo expansion haematopoietic stem cell niches. Nat Rev stem cells secreting angiopoietin-like-5 sup- fi of human adult stem cells capable of primary Immunol 2017. e-pub ahead of print 12 port ef cient expansion of human hemato- and secondary hemopoietic reconstitution. June 2017; doi:10.1038/nri.2017.53. poietic stem cells without compromising Exp Hematol 2003; 31:261–270. 7WilsonA,TrumppA.Bone-marrow their repopulating potential. Stem Cells Dev – 3 Heike T, Nakahata T. Ex vivo expansion of haematopoietic-stem-cell niches. Nat Rev 2011; 20:13711381. hematopoietic stem cells by cytokines. Bio- Immunol 2006; 6:93–106. 11 Yong KS, Keng CT, Tan SQ, Loh E, chim Biophys Acta 2002; 1592:313–321. 8 Weidner CI, Walenda T, Lin Q, Wolfler MM, Chang KT, Tan TC et al. Human CD34(lo) 4 Dahlberg A, Delaney C, Bernstein ID. Ex vivo Denecke B, Costa IG et al. Hematopoietic CD133(lo) fetal liver cells support the expan- expansion of human hematopoietic stem stem and progenitor cells acquire distinct sion of human CD34(hi)CD133(hi) hemato- and progenitor cells. Blood 2011; 117: DNA-hypermethylation during in vitro poietic stem cells.
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