Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy

Abstract

Intercellular communications play a major role in tissue homeostasis and responses to external cues. Novel structures for this communication have recently been described. These tunneling nanotubes (TNTs) consist of thin-extended membrane protrusions that connect cells together. TNTs allow the cell-to-cell transfer of various cellular components, including proteins, RNAs, viruses, and organelles, such as mitochondria. Mesenchymal stem cells (MSCs) are both naturally present and recruited to many different tissues where their interaction with resident cells via secreted factors has been largely documented. Their immunosuppressive and repairing capacities constitute the basis for many current clinical trials. MSCs recruited to the tumor microenvironment also play an important role in tumor progression and resistance to therapy. MSCs are now the focus of intense scrutiny due to their capacity to form TNTs and transfer mitochondria to target cells, either in normal physiological or in pathological conditions, leading to changes in cell energy metabolism and functions, as described in this review.

Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer

“…Mitochondria‐containing microvesicles were shown to bud from both the ends of TNTs and from the MSC cell body, with engulfment of some of the microvesicles by the epithelial cells. We observed extensive MSC‐derived mitochondrial‐GFP labeling 25‐40 μm (3‐4 islet cell layers) into the 3D human islet architecture, consistent with the notion of organelle transfer through TNTs, which have lengths of several cell diameters . We also detected TNT‐like structures, composed of F‐actin, spanning between the MSCs and neighboring β‐cells.…”

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

“…Hence, MitoT might represent an amenable system to study functional changes in T cells while enabling improved cell-based treatments, since MSCs are a main cell source for MitoT [12]. MT status not only fuels active lymphocytes but as our data indicate also provides guidance for proliferation, migration, and cell fate decisions.…”

“…MT status not only fuels active lymphocytes but as our data indicate also provides guidance for proliferation, migration, and cell fate decisions. Hence, MitoT might represent an amenable system to study functional changes in T cells while enabling improved cell-based treatments, since MSCs are a main cell source for MitoT [12]. The scope of such immunometabolic and regulatory change has been in part addressed by Chen et al [13] who evidenced that UC-MSCs tended to correct the mitochondrial respiratory dysfunction and increased T-cell apoptosis of SLE patients, in concomitance with MitoT to PBMCs in vitro.…”

“…MT trafficking was found to be independent of pre-conditioning, proinflammatory, or anti-oxidant treatment of MSCs or mitogen stimulation of target PBMCs. Mesenchymal stem cells are known to establish tunneling nanotube connections (TNTs) with target cells, including cardiomyocytes, endothelial cells, and tumor cells [12]. Also, TNT formation was described between MSCs and macrophages leading to an enhanced phagocytosis activity [6].…”

Mast cell‐neural interactions contribute to pain and itch

“…Murine mast cell TNTs were observed first with costimulation of FcεR1 with CCR1 and MIP‐1α . Distinct differences between EVs and nanotubes and their function are still emerging, but they have been implicated in tumor progression and resistance to therapy, which can be important in cancer pain . In the present context, TNTs offer another mechanism for mast cells to interact directly with neural, vascular, and immune systems as all of these systems engage in TNT formation.…”