Extrinsic Regulation of Hematopoietic Stem Cells and Lymphocytes by Vitamin A
- 51 Downloads
Purpose of Review
Vitamin A and its receptors, retinoic acid receptors (RARs), are key regulators of hematopoiesis. This review focuses on the extrinsic regulation of hematopoiesis by retinoids, predominantly focusing on studies in mice, but also highlighting some of the studies performed using human hematopoietic stem cells (HSCs).
RARγ has key roles in regulating B and T lymphocytes via distinct bone marrow mesenchymal cells and thymic microenvironment cells, respectively. The hematopoietic phenotypes caused by vitamin A deficiency are largely due to microenvironment-induced phenotypes that occur due to RARγ deficiency. Studies using human HSCs have also revealed that the biologically active form of vitamin A increases the HSC-support potential of immature mesenchymal cell lines.
Distinct roles have been revealed for different vitamin A receptors in regulating hematopoiesis. Further elucidation of the mechanisms whereby the RARs extrinsically regulate immune cells and HSCs may provide insights leading to the development of improved therapeutics to manipulate the numbers of these cells in normal and diseased states.
KeywordsRetinoids Retinoic acid receptors Bone marrow microenvironment cells Hematopoietic stem cells Lymphocytes
This review was supported in part by grants from the National Health and Medical Research Council of Australia (1127551 to LEP) and the Victorian State Government Operational Infrastructure Support Program (to St. Vincent’s Institute of Medical Research).
Compliance with Ethical Standards
Conflict of Interest
Chacko Joseph, Alanna C. Green, Diannita Kwang, and Louise E Purton declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 9.•• Grace CS, Mikkola HKA, Dou DR, Calvanese V, Ronn RE, Purton LE. Protagonist or antagonist? The complex roles of retinoids in the regulation of hematopoietic stem cells and their specification from pluripotent stem cells. Exp Hematol. 2018;65:1–16. Thoroughly reviews the roles of retinoids in regulating the self-renewal of HSCs and their specification from pluripotent stem cells. CrossRefGoogle Scholar
- 10.•• Joseph C, Nota C, Fletcher JL, Maluenda AC, Green AC, Purton LE. Retinoic acid receptor γ regulates B and T lymphopoiesis via nestin-expressing cells in the bone marrow and thymic microenvironments. J Immunol. 2016;196:2132–44. Reveals that RARγ extrinsically regulates the production of B and T lymphocytes via nestin-expressing microenvironment cells. CrossRefGoogle Scholar
- 14.Harika R, Faber M, Samuel F, Kimiywe J, Mulugeta A, Eilander A. Micronutrient status and dietary intake of iron, vitamin A, iodine, folate and zinc in women of reproductive age and pregnant women in Ethiopia, Kenya, Nigeria and South Africa: a systematic review of data from 2005 to 2015. Nutrients. 2017;9(10).CrossRefGoogle Scholar
- 38.• Joseph C, Quach JM, Walkley CR, Lane SW, Lo Celso C, Purton LE. Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell. 2013;13(5):520–33. Discusses different transgenic mouse models and imaging methods used to study HSC niches. CrossRefGoogle Scholar
- 40.•• Kusumbe AP, Ramasamy SK, Itkin T, Mae MA, Langen UH, Betsholtz C, et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature. 2016;532(7599):380–4. Identifies distinct endothelial cells in bone marrow and reveals age-dependent roles in the regulation of HSCs by the vascular niche. CrossRefGoogle Scholar
- 41.•• Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227–30. Reveals that CXCL12 produced by distinct microenvironment cells has different roles in regulating HSCs. CrossRefGoogle Scholar
- 49.•• Zhou BO, Yu H, Yue R, Zhao Z, Rios JJ, Naveiras O, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19(8):891–903. Shows that adipocytes are a major source of SCF and are essential in regeneration of bone marrow after injury. CrossRefGoogle Scholar
- 51.•• Green AC, Rudolph-Stringer V, Chantry AD, Wu JY, Purton LE. Mesenchymal lineage cells and their importance in B lymphocyte niches. Bone 2018; in press. A thorough review of the roles of mesenchymal cell lineages in the regulation of B lymphopoiesis. Google Scholar
- 62.•• Green AC, Rudolph-Stringer V, Straszkowski L, Tjin G, Crimeen-Irwin B, Walia M, et al. Retinoic acid receptor γ activity in mesenchymal stem cells regulates endochondral bone, angiogenesis and B lymphopoiesis. J Bone Miner Res 2018;in press. Reveals that RARγ activity in limb bud mesenchymal stem cell-derived microenvironment cells alters the trabecular bone, chondrocytes, bone marrow sinusoids, and B lymphocytes in mice. Google Scholar
- 74.•• Ghiaur G, Yegnasubramanian S, Perkins B, Gucwa JL, Gerber JM, Jones RJ. Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling. Proc Natl Acad Sci U S A. 2013;110(40):16121–6. Reveals that microenvironment-produced CYP26 regulates human HSC maintenance. CrossRefGoogle Scholar