Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Nov 14:7:502.
doi: 10.3389/fimmu.2016.00502. eCollection 2016.

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

Larisa V Kovtonyuk  1 , Kristin Fritsch  1 , Xiaomin Feng  2 , Markus G Manz  1 , Hitoshi Takizawa  2
Affiliations
Review

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

Larisa V Kovtonyuk et al. Front Immunol. .

Abstract

All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of "Inflamm-Aging," or inflammation-associated aging of hematopoiesis.

Keywords: ageing; cytokine; hematopoietic stem cell; inflammation; niche; pathogen recognition receptor.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Inflammation- and aging-associated changes in hematopoiesis. (A) In steady state, platelet-biased HSCs are at the top of the hematopoietic hierarchy and are able to generate myeloid-biased and lymphoid-biased HSCs. In turn, myeloid-biased HSCs can generate both balanced- and lymphoid-biased HSCs, whereas lymphoid-biased HSCs do not generate their myeloid-biased counterparts. Platelet-biased HSCs have the potential to repopulate platelet populations faster than other HSC subsets. Myeloid-biased HSCs preferentially give rise to myeloid lineage cells through myeloid committed progenitors. Balanced HSCs make equal contributions to both myeloid and lymphoid lineages. Lymphoid-biased HSCs predominantly generate lymphoid over myeloid lineage cells through lymphoid-committed progenitors. Dashed lines represent the potential of one HSC subset to generate another HSC subset. Solid lines represent differentiation potential. (B) Inflammation enhances myeloid lineage production, including myeloid progenitors and mature myeloid cells, leading to myeloid bias in hematopoiesis. (C) During the processes of aging, myeloid-biased HSCs increase and produce more myeloid than lymphoid cells. Red arrows indicate the dominant differentiation pathway. Dashed lines represent a potential pathway. Solid lines represent the differentiation potential shown previously. The thickness of the lines reflects the relative contributions to each lineage commitment.
Figure 2
Figure 2
Impacts of aging on immunity and hematopoiesis. During aging, myelopoiesis results in the domination of hematopoiesis over lymphopoiesis due to increased numbers of myeloid-biased HSCs, myeloid progenitors, and myeloid cells, while the pool consisting of B and T cells shrinks. These hematopoietic changes result in increased dependence of the immune system on innate rather than acquired immunity, with an enhanced basal level of inflammation, increasing the risk of myeloid neoplasia or spontaneous anemia.
Figure 3
Figure 3
Responses of hematopoietic stem and progenitor cells (HSPCs), and non-hematopoietic bone marrow cells to infection. HSPCs and non-hematopoietic cells in bone marrow (BM), such as mesenchymal stromal cells (MSCs) and endothelial cells, express both cytokine and pattern recognition receptors (PRRs) on their surfaces. In response to infections in peripheral tissues, (a) immune cells or endothelial cells secrete pro-inflammatory cytokines that migrate to the BM and stimulate the respective receptors expressed on HSPCs, thereby inducing their proliferation, migration and/or differentiation; (b) alternatively, migrating cytokines also can act on MSCs or endothelial cells to enhance their pro-inflammatory cytokine production; and (c) some pathogen-derived molecules reach the BM and activate HSPCs directly through PRRs or indirectly through pro-inflammatory cytokines produced by PRR expressing MSCs or HSPCs.
Figure 4
Figure 4
Potential hallmarks of inflamm-aging. The schematic figure highlights similarities between aging and inflammation-associated changes in hematopoiesis and hematopoietic stem cells: (a) extrinsic factors include bone marrow niche alterations, metabolic changes, tissue damage/repair, and infection/microbiome; (b) intrinsic factors include proliferative stress, telomere attrition/genomic instability, dysregulated autophagy, metabolic stress, and dysregulated autophagy.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fliedner TM, Graessle D, Paulsen C, Reimers K. Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure. Cancer Biother Radiopharm (2002) 17:405–26.10.1089/108497802760363204 - DOI - PubMed
    1. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell (2005) 121:1109–21.10.1016/j.cell.2005.05.026 - DOI - PubMed
    1. Nakamura-Ishizu A, Takizawa H, Suda T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development (2014) 141:4656–66.10.1242/dev.106575 - DOI - PubMed
    1. Takizawa H, Regoes RR, Boddupalli CS, Bonhoeffer S, Manz MG. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. J Exp Med (2011) 208:273–84.10.1084/jem.20101643 - DOI - PMC - PubMed
    1. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell (2008) 135:1118–29.10.1016/j.cell.2008.10.048 - DOI - PubMed

LinkOut - more resources