EV-Mediated Intercellular Interactions in Stem Cell and Plasticity: History
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Contributor:
Natalia Polyakova
,
Maria Kalashnikova
,
Alexander Belyavsky

In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism’s survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular communications in determining the fate of cells, as well as their differentiation and plasticity. For a long time, it was believed that the properties and behavior of cells were primarily governed by the interactions of secreted or membrane-bound ligands with corresponding receptors, as well as direct intercellular adhesion contacts. 

  • intercellular
  • intercellular communications
  • intercellular interactions
  • stem cells
  • plasticity

1. Introduction

In modern biomedicine, the emergence of new cell therapy approaches potentially capable of significantly expanding the possibilities of classical pharmacology determines the increasing interest in the deep transformation of cellular properties. Particular attention is now being paid to the study of intercellular interactions and communications, which, for example, are primarily responsible for the therapeutic effects of stem cells (SCs) and the phenomenon of education of normal cells by tumors in vitro and in vivo [1][2][3].
Four types of communications by animal cells are universally accepted, namely, endocrine, paracrine and contact signaling, as well as nervous transmission [4][5][6][7][8]. Endocrine signaling is mediated by the production of hormones in the endocrine glands and their systemic distribution to distant target cells. Paracrine signaling has a narrower range and is mediated by the local action of paracrine signaling substances secreted by cells into intercellular spaces. In contact signaling, cell surface molecules bind to a receptor on a neighboring cell, while nerve signal transmission is carried out along axons to distant target cells. 
Since extracellular vesicles—in particular, exosomes—have significant biotechnological potential but are also involved in pathogenesis, the study of the mechanisms underlying the maturation and release of exosomes may be important for the development of new therapeutic approaches in medicine. In preclinical trials, the effects of microvesicles and exosomes obtained from conditioned stem cell media are comparable to the regenerative effects obtained with SC transplantation [9][10][11]. At the same time, the clinical use of stem cells themselves is still associated with problems resulting primarily from their low survival rate after transplantation [12][13].

2. Extracellular Vesicles in the Bone Marrow Niche as Regulators of HSC Quiescence, Expansion and Differentiation

In maintaining homeostasis and regulating the functions of many, if not all, types of stem cells (SCs), the so-called niche plays a decisive role, the specific components of which create a favorable and carefully controlled environment ensuring the survival and proper functioning of SCs. The bone marrow, along with hematopoietic stem cells (HSCs) and progenitors, as well as endothelial cells, also contains MSCs and cells derived from MSCs, such as osteoblasts and adipocytes, which, in various combinations and with the participation of the extracellular matrix, constitute a specialized niche that regulates the state and functioning of HSCs [14]. Back in the 1960s, MSCs were discovered as non-hematopoietic cells of the bone marrow microenvironment supporting the process of hematopoiesis [15]. The interaction between MSCs and HSCs controls their differentiation and protects them from apoptosis, thus promoting the self-renewal and maintenance of HSCs [16][17].
Although the roles of paracrine signaling and adhesive interactions in HSC-niche intercellular interactions are firmly established (see, for example [14][18][19][20]), the roles of various types of non-classical communications remain to be elucidated. Nevertheless, it has been reliably established that a significant role in the modulation of the bone marrow niche is played by extracellular vesicles that can change the biology of HSCs and progenitor cells [21][22]. Ex vivo studies show that MSC microvesicles contain effector molecules, including Wnt and Hedgehog morphogens, which regulate SC self-renewal, proliferation and differentiation [23][24]. Moreover, microRNAs of MSC vesicles are actively involved in the regulatory processes in HSCs. In particular, these vesicles contain miRNAs that suppress the production of many Wnt inhibitors in HSCs and precursors, which, in ex vivo cultures, leads to an increase in the number of colony-forming units [25]. EVs from MSCs also increase CXCR4 expression in cord blood HSCs, stimulating their homing to the bone marrow [26]. Finally, the role of MSC vesicles in the regulation of hematopoiesis through innate immune mechanisms has been identified. In particular, MSC microvesicles are able to stimulate the expansion of HSCs and their myeloid differentiation through interaction with TLR4 (Toll-like receptor 4) [27].
A study by Salvucci et al. [28] found that granulocyte colony stimulating factor (G-CSF) promotes the accumulation of miR126-containing vesicles in the bone marrow extracellular compartment. Vesicle-delivered miR126 reduces surface expression of VCAM1 in HSCs and progenitor, stromal and endothelial cells, thus regulating the mobilization and movement of HSCs and progenitor cells between the bone marrow and peripheral sites. Another study established that exosomes produced by IL-4-polarized M2 macrophages have an immunomodulatory function and are able to limit the expansion of hematopoietic progenitors and reduce inflammation [29].
In recent years, considerable attention has been paid to the aging of the hematopoietic system, studied primarily in mouse models [30][31]. Recent data show both the role of hematopoietic niches in aging and the participation of extracellular vesicles in this process. In particular, H2O2 levels in the bone marrow microenvironment have been shown to increase with age, while treatment of bone marrow stem cells with H2O2 increased the amount of miR-183-5p in extracellular vesicles. This in turn caused a decrease in cell proliferation and aging, as well as reduction in heme oxygenase 1 levels (Hmox1) [32]. In addition, endocytosis of miR-183-5p+ vesicles by young bone marrow stromal cells leads to inhibition of their proliferation and suppression of osteogenic differentiation.
It should be noted that the effects of extracellular vesicles on the aging of the human hematopoietic system, in contrast to the murine system, have been little studied. Grenier-Pleau et al. [33] characterized blood EVs in people aged 20–85 years, demonstrating that while EVs’ external parameters, such as size, were constant with aging, the protein profiles of EVs did change. As a result, EVs from donors older than 40 years stimulated HSCs, in contrast to the EVs from younger persons. A new study [34] examined the modulation of cell cycle activity and clonogenicity of HSCs by extracellular vesicles. EVs from young MSCs were able to support the expansion of HSCs in vitro, while vesicles from old MSCs did not have a positive effect on cell survival and proliferation. This was accompanied by changes in gene expression, since in HSCs treated with vesicles of old MSCs, a decrease in the expression of the tumor suppressors PTEN and CDKN2A was observed. The above data are in good agreement with the notion that aging is associated with the risks of developing cancer and is caused by serious changes in the functions and phenotypes of cells, induced, among other things, by horizontal or epigenetic regulation of cell life processes.

3. Extracellular Vesicles in Oncogenesis

Leukemic exosomes have various effects on the viability and differentiation of HSCs. Thus, exosomes of acute myeloid leukemia are able to change the function of HSCs or bone marrow stromal cells, transferring miR-155 to HSCs and participating in slowing down their differentiation due to a decrease in c-MYB expression [35]. In chronic lymphocytic leukemia, microvesicles activate the AKT pathway and elevate the production of hypoxia-induced factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF), changing the bone marrow niche in a malignant direction [36].
A large number of data have convincingly demonstrated that EVs of tumor cells have a significant effect on the development of tumors—in particular, they recruit and remotely modify normal body cells in the pre-metastatic niche during metastasis and induce angiogenesis and other processes associated with tumor growth [37][38][39]. Thus, the primary tumor has the ability to selectively modify the microenvironment of distant organs before metastasis, and both vesicles of tumor origin and bone marrow cells are involved in this process [40][41][42].
Currently, active research is being conducted in the field of hematopoiesis suppression in multiple myeloma [43][44][45][46]. The critical role of EVs in the pathogenesis of multiple myeloma was demonstrated in a recent study where extracellular vesicles derived from multiple myeloma cells (MM-EVs) transmitted oncogenic NOTCH2 receptors and increased NOTCH signaling in distant targets, affecting the pro-tumorogenic behavior of endothelial cells and osteoclast precursors [47]. Another study established that MM-EVs activate proliferation and induce an increase in the frequency of HSCs and early progenitors, with a simultaneous decrease in the frequency of later progenitors and impaired colony formation by HSPCs [48]. These data are in good agreement with the recent findings of Lopes et al. [49] that MM-EVs are able to modulate the immune microenvironment of the bone marrow, thereby changing the expression of key factors involved in the regulation of the antitumor activity of T cells (for example, IC PD-1 and CTLA-4).
The pathological effect of tumor-derived EVs is mediated by their molecular cargo, which differs significantly from that of normal ones. Thus, exosomes from the plasma of cancer patients contain such markers as PD-1/PD-L1, TRAIR/TRAIL and Fas/FasL [50]. The permanent components of tumor exosomes also include miRNAs, oncogenic DNA sequences (HRAS, BCR-ABL and KRAS), cell adhesion molecules, as well as other proteins [51]. In metastatic prostate cancer, for example, tumor extracellular vesicles migrate to the bone, where the absorption of miR-378a-3p from these vesicles by bone marrow macrophages initiates the process of osteolysis along the Dyrk1a/Nfatc1 pathway, which in turn contributes to an increase in Angptl2 secretion and tumor progression [52].
The key role of extracellular vesicles in communication between adipocytes and breast cancer cells was shown in a recent study describing a new mechanism that enhances the malignant potential of breast cancer cells [53]. The metastatic effects of extracellular vesicles were mediated by the induction of HIF-1α and could be neutralized by the HIF-1α inhibitor KC7F2 or suppression of its expression. Interestingly, extracellular vesicles from undifferentiated adipocytes did not induce HIF-1α expression and did not contribute to tumor progression.
Among other things, exosomes and microvesicles of tumor cells are capable of reprogramming mesenchymal stem cells into cells supporting tumors and even tumor-like cells [54][55][56][57]. Thus, tumor exosomes carrying TGF-β1 and VEGF induced reprogramming of MSCs into pro-invasive and pro-angiogenic myofibroblasts [58][59][60]. Gyukity-Sebestyén et al. [54] showed that MSCs in the process of communication with metastatic melanoma cells via exosomes are subject to malignant reprogramming that converts them into melanoma-like, PD-1 overexpressing cell populations. This identified a tumorigenic protein signaling network that includes such key regulators as RAF1, MET, BCL2, PD-1 and mTOR in MSCs treated by exosomes. These results correlate with earlier findings by Kleffel et al. [61] that in aggressive melanoma populations, high expression of PD-1 and activation of the mTOR signaling pathway contributed to tumor progression, while inhibition of PD-1 signaling attenuated melanoma aggressiveness and metastasis. In another study, the effects of exosomes from K562 chronic myeloid leukemia cells on the gene expression, cytokine secretion and redox potential of bone marrow MSCs and macrophages have been convincingly demonstrated [62]. Accumulated data indicate that, when exposed to tumor vesicles, MSCs acquire a significant number of functions characteristic of cancer cells, including migration to the tumor site, production of pro-inflammatory cytokines, stimulation of angiogenesis and tumor growth, induction of the epithelial-mesenchymal transition and suppression of immune effector cells [63][64][65]. The reprogramming of MSCs by extracellular vesicles of tumor origin is thus a continuous process serving the needs of growing and metastasizing tumors.
On the other hand, many antitumor effects are also known to be exerted by vesicles of MSCs and other stem cells. Phetfong et al. [66] recently established that BM MSC EVs suppressed cell proliferation and induced apoptosis of chronic myeloid leukemia (K562) and acute promyelocytic leukemia (NB4) cells in vitro. According to one of the latest meta-analyses, MSC-EVs had a mixed response to tumor progression. However, significant suppression of tumor growth was observed frequently with vesicles from MSCs that overexpressed anti-tumor RNA [67]. Finally, the efficiency of antitumor therapy can be increased by using exosomes derived from osteogenic differentiating MSCs, which induce osteogenic differentiation of cancer stem cells and reprogram them into non-tumor cells [68].

4. The Use of Extracellular Vesicles for the Induction of Plasticity and Transdifferentiation of Cells

Adult resident SCs are normally able to differentiate into several different cell types, which is vital for tissue homeostasis [69]. In this sense, SCs already have an inherent plasticity potential, in contrast to mature differentiated cells, which are expected to maintain their specific identities. However, the plasticity of SCs and other cells, in the true sense, implies substantial expansion of their differentiation potential beyond what is available to them normally.
The substantial effect of EVs on the plasticity of SCs and other cells was first established in the laboratories of M. Ratajczak [70] and P. Quesenberry [71]. In one study [70], microvesicles of embryonic SCs were demonstrated to significantly increase survival and stimulate the expansion of hematopoietic progenitors, as well to increase the expression of the pluripotent markers Oct4, Nanog, and Rex-1 and the early hematopoietic markers Scl, HoxB4, and GATA 2. Another study [71] revealed that microvesicles of cells from radiation-damaged lungs can affect bone marrow cells, causing them to express genes characteristic of lung epithelial cells, as well as increase their ability to produce type 2 pneumocytes after transplantation. Subsequent studies by the Quesenberry laboratory showed that the described effects result in long-term and stable transcriptome changes [72]. Moreover, these effects were dependent on the stage of the cell cycle [73].
A striking example of stem cell plasticity mediated by exposure to EVs is the recent work on the differentiation of human adipose stem cells (HASCs) into white and beige adipocytes, which was induced by vesicles isolated from HASCs during adipogenic differentiation into the different adipocyte types [74]. These experiments demonstrated the presence of factors in EVs that promote the differentiation of stem cells in one direction or another in vitro and in vivo.
The potential of extracellular vesicles in cell transdifferentiation was convincingly shown in a recent study [75], where a very high efficiency of reprogramming fibroblasts into functional cardiomyocytes was achieved by using vesicles from embryonic SCs in which cardiomyogenic differentiation was induced. In another study, it was shown that vesicles from two different types of epithelial cells are able to induce cross-transdifferentiation of these cells [76]. Extracellular vesicles can thus be considered very promising tools for targeted long-term changes in cell properties and induction of their plasticity.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24076455

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