Inflammation and mesenchymal stem cell aging

Abstract

In adults, mesenchymal stromal cells contain tissue-specific multipotent stem cells, MSC, which can be found throughout the body. With advancing age, tight controls of regulatory networks, which guide MSC biology, gradually deteriorate. Aberrations within the MSC microenvironment such as chronic inflammation eventually lead to adverse manifestations, such as the accumulation of fat deposits in bone and muscles, impaired healing and fibrosis after severe injury, or altered hematopoiesis and autoimmunity. MSC can also specifically interact with a large variety of immune cells, and in doing so, they secrete cytoprotective and immunoregulatory molecules, which together with intercellular contacts mediate immune modulatory processes. This review comprehends the current knowledge regarding molecular mechanisms and cellular interactions that occur in stem cell niches, which are jointly shared between MSC and hematopoietic stem and progenitor cells, as well as those intracellular interdependences taking place between mesenchymal and a wide variety of hematopoietic progeny in particular T lymphocytes, which eventually perturb tissue homeostasis and immunology at advanced age.

Figure 1

Inflammatory ambiences governing MSC polarization, progenitor development and regulatory cues. Mesenchymal stem cells (MSC) nest together with hematopoietic stem cells (HSC) in a common niche comprising specific structural features such as a high density of blood vessels (BV). There, MSC release bioactive molecules into their microenvironment such as the chemokine CXCL12, interleukin 7 (IL7) angiopoietin-1 (ANG1) or bone sialoprotein 1 (BSP1, also called osteopontin). Ambient factors regarding acute or chronic inflammatory insults confound the MSCs’ activity to

1. (i)

   secrete indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL6), interleukin 8 (IL8), interleukin 10 (IL10), prostaglandin E-2 (PGE₂), transforming growth factor beta (TGFβ) after activation of toll-like receptors 3 or 4 (TLR3, TLR4) to act on immune cells (IC) to trigger specific T helper (Th) cell responses;

2. (ii)

   to convey under low or transient inflammatory stimuli the differentiation of osteoblasts (OB) while at the same time checking progression of adipogenic cells (AC); contrastingly within a chronically inflamed periphery, the osteogenic fate of MSC progeny is stalled and adipogenic differentiation upholstered; the latter further propagate an inflammatory milieu through further excretion of tumor necrosis factor alpha (TNFα) or adiponectin;

3. (iii)

   to support the emergence and diversity of hematopoietic precursor cells (HPC) through strong osseous structures in a protected environment while stem cell proximities destined to degenerate by adipose outgrowth hinder the advent of HPC formation.

Deteriorating long-lasting chronic inflammation is frequently observed in biological communication systems at advanced age, for which the frequently used expression ‘inflamm-aging’ has been coined.