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Marrow stem cells enterprising toward aging: a journey among receptors, cytokines, signaling, “fatty” stores and lifestyle

The aging immune system is associated with reduced lymphopoiesis, increased inflammation, and bone marrow diseases due to alterations in self-renewing haematopoietic stem cells (HSCs). In a recent investigation, researchers gfrom the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, developed a treatment to restore the immunological system to a younger condition, with fewer myeloid-biased output-stem cells (my-HSCs), more HSCs and a balanced generation of myeloid and lymphoid lineage cells (bal-HSCs). During childhood, bal-HSCs predominate, thereby facilitating lymphopoiesis and adaptive immune responses. Age increases my-HSCs, which reduces lymphopoiesis and enhances myelopoiesis. Myeloid-HSC origin and possible interconversions are unclear; however, removing my-HSCs in aged mice may reverse the aging phenotype.

The researchers investigated whether antibody-regulated reduction of my-HSCs may cure age-related immunological reductions by restricting myeloid cell-induced inflammation and restoring lymphopoiesis. Several cell-surface antigen molecules were developed and validated to identify potential targets for therapeutic my-HSC reduction. Several my-HSC antigens, including neogenin 1 (NEO1), cluster of differentiation 62p (CD62p), and CD150, were subsequently targeted to determine their role in reducing my-HSC levels. To establish the role of CD150 targeting, the ability of CD150-targeted antibodies to reduce my-HSCs in vivo was assessed. To target CD62p or NEO1, goat anti-mouse NEO1 antisera was mixed with anti-CD47 and anti-KIT antibodies. T-cell subsets were analyzed using canonical markers or cluster-based analysis and common lymphocyte progenitors (CLPs) were measured in bone marrow.

Antibody-mediated reduction of my-HSCs in elderly mice restored young immune system characteristics, such as increased CLPs, naïve T-cells, and B-cells, while lowering immunological decline indicators associated with aging. Depletion of my-HSCs in old mice increased primary and secondary adaptive immune responses to viral infection. Twelve potential genes that encode cell-surface proteins significantly expressed in aged HSCs and my-HSCs were identified. Moreover, CD150, CD4, CD6, CD62p20, and NEO1 were identified as markers for my-HSCs. Antibodies to CD41 and NEO1 enhanced the frequency of my-HSC staining, thus indicating myeloid bias. CD62p targeting resulted in the highest my-HSC enrichment. The most abundant protein molecules on my-HSCs were NEO1, CD41, and CD62p. Anti-CD150 antibodies significantly reduced my-HSCs in mice, thereby increasing naïve T-cell and mature B-cell levels.

In aged mice, CD4+ T lymphocytes with an exhausted phenotype (PD1+ CD62L-) grew more than those with a non-exhausted phenotype (PD1- CD62L+). Aged mice also acquired age-associated B-cells associated with impaired humoral immunity. Antibody training reduced CD4+ PD1+ CD62L- cells, the levels of pro-inflammatory proteins including interleukin-1 alpha (IL-1α), and chemokine ligand CXCL5, which were higher in elderly animals. Interleukin-1 could be one of the main factors responsible for the immune aging that occurs with the biological aging iteself. IL-1, in fact, is the pyrogen or the main mediator of fever in case of infections, among the main mediators that pushes the immune system to react by organizing responses and the secondary synthesis of antibodies. It is likely to believe, therefore, that it is the “use stress” to which the immune system is subjected during the course of life that causes its own functional exhaustion.

It is known to scientists, among other things, that there is a phenomenon of stressful replication which stem cells forcibly undergo following exposure to stressful agents of the immune system, including excessive antigenic stimulation. While on the one hand, this can “exhaust” T lymphocyte populations, this does not spare those that produce antibodies, i.e. B lymphocytes. B lymphopoiesis declines with age, and this decline correlates with increased adipose tissue in the bone marrow. Also, adipocyte-derived factors are known to inhibit B lymphopoiesis. Indeed, a research from Kennedy et al. (2015), showed that myeloid-derived suppressor cells (MDSCs) inhibit B lymphopoiesis via soluble factors, and by cytokine array IL-1 was identified as a leading factor. IL-1 is also an adipokine, i.e. a chemokine produced in the adipose tissue and scientists already know its importance in guiding pathologic phenomena like insulin resistance, chronic inflammation and blood coagulative issues.

Excessive white adipose tissue is considered a risk factor for the most common clinical entities nowadays, including diabetes mellitus, cardiovascular diseases, some forms of cancer and even neurological diseases like Alzheimer dementia. In all these pathologies, immune intervention both directly and indirectly has been proven and the presence of chronic inflammation also determined by concomitant factors linked to lifestyle (smoking, alcohol abuse, high-calorie diet, etc.) can contribute to both trigger the problem than maintain it. Therefore, maintaining an “inflammatory” lifestyle that promotes chronic inflammation, both through an excess of white adipose tissue and through a dysregulation of immune responses, can undoubtedly contribute to the phenomenon of inflammaging and the progressive loss of immune function. That interleukin-1 is among the factors underlying these changes can also be deduced from the type of cellular signal.

In response to ligand binding of the IL-1 receptor, intracellular signaling starts a complex sequence of combinatorial phosphorylation and ubiquitination events through anchored adaptors like MyD88, TIFA and kinases like IRAK1, IRAK4 e TAK-1. This results in activation of NF-kB transcription factor and the JNK and p38 mitogen-activated protein kinase pathways which, cooperatively, induce the expression of inflammatory target genes. Of note, most intracellular components that participate in the cellular response to IL-1 also mediate responses to other cytokines, Toll-like-receptors (TLRs) and many forms of cytotoxic stresses. Indeed, IL1R and most Toll receptors share MyD88 and IRAK1 as imediate downstream effectors. Prolonged JNK/p38 kinase activation, may lead either to senescence or staminal clone erasing through programmed cell death. Apoptosis, in turn, might contribute to the progressive exaustion of hematopotietic potential in bone marrow.

On the contrary, stem cell-aiding growth factors like G-CSF, GM-CSF, FGF-2, PDGF, HGF and others), act with tyrosine kinase-based signaling either in intrinsic (RTKs) and extrinsic modality. RTKs, indeed, may act also with other non-receptorial tyrosine kinases (c-Src, c-Fyn, c-Lck, c-Lyn and others) to phosphorylate dowstream adaptors and enzymes. The critical point is the activation of the proto-oncogene H-Ras. This small G protein induce the mitogenic protein kinase module (MAPK/ERKs) along with cell death-suppressive pathways (PI3K-Akt and Rsk2-mTOR) to allow gene espression related to cell proliferation and survival. Bone marrow stem cells do utilize the MAPK signaling mostly to induce self-renewal instead of cellular replication. Within the singaling pathways used by growth factors (e.g. PDGF or IL-3) to induce stem cell proliferation there is also a transient rise in reactive oxygen species (ROS).

Oxidative stress is recognized as the a main trigger for cellular aging through either direct (chromatin damage) or indirect (change in genetic and epigenetic changes). Rapid variations in ROS are required to general and regular cell responses; in good conditions, antioxidants like glutathione and scavenging enzymes (peroxidases, SOD, etc.) get rid of them to shut off the biological response. ROS are among the mediators of cytokines like IL-1, TNF-alpha, IFN-gamma and G-CSF which induce inflammation. HSCs are robustly responsive to inflammatory conditions during infections and various molecular signals can influence them. They express certain receptors for recognition of pathogen patterns such as Toll-like receptor 4 (TLR4) and initiate signal transduction that can alter HSC functions. However, a poor lifestyle triggers inflamm-aging and the expansion of bone marrow stem clones as a reaction.

In time, however, a sustained presence of he aforementioned inflammatory cytokines may negatively affect the clonal expansion and self-renewal. Like IL-1, infact, the intracellular signaling is mostly committed toward the activation of stress kinases (JNK and/or p38) which rarely may induce replication or self-renewal. Only TNF-alpha contemplate the possibility to activate MAPK/ERK signaling amidst the JNK or p38 “cousins”. Indeed, TNF-alpha is among the few cytokines to be able to promote hemopoietic progenitors to expand and produce neutrophil granulocytes, which are the first line of defense against infections. In the elderly, indeed, neutrophils are constantly produces at the expense of other cellular types, like T cells which coordinate the subsequent immune response. Therefore, we can imagine inflamm-aging as a primary immune response (mediated by neutrophils) which cannot properly go to a completion for lack of lymphocytic takover.

This primary response converts itself to inflamm-aging due to the biological actions of neutrophils and their “oxidative burst”, which is not easily faded and followed by other cell types and responses. Endogenous enhancers or inhibitors of this cellular bias that happens during bone marrow progenitor bias are known; yet, the knowlegde about their huge cellular biology and biochemistry of their signalings and cross-talks is far to be thorough. A better understanding of them will allow medical practice to find natural ways to enhance immunity in the old age; or to include genetic manipulation to support the same purpose until that “knowledge” is complete.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Ross JB, Myers LM et al. Nature 2024; in press.

Gulati GS et al. PNAS USA 2021; 116:25115-125.

Maryanovich M et al. Nature Med. 2018; 24:782-91.

Palomo J et al. Cytokine. 2015 Nov; 76(1):25-37.

Eom YW et al. BBRC 2014 Feb 28; 445(1):16-22.

Pang WW et al. PNAS USA 2011; 108, 20012–17.

Weber A et al. Sci Signal 2010 Jan 19; 3(105):cm1.

Rossi DJ et al. PNAS USA 2005; 102, 9194–9199.

Morrison SJ et al. Nature Med. 1996; 2:1011-1016.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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