Stem cell niches and endogenous electric fields in tissue repair

Abstract

Adult stem cells are responsible for homeostasis and repair of many tissues. Endogenous adult stem cells reside in certain regions of organs, known as the stem cell niche, which is recognized to have an important role in regulating tissue maintenance and repair. In wound healing and tissue repair, stem cells are mobilized and recruited to the site of wound, and participate in the repair process. Many regulatory factors are involved in the stem cell-based repair process, including stem cell niches and endogenous wound electric fields, which are present at wound tissues and proved to be important in guiding wound healing. Here we briefly review the role of stem cell niches and endogenous electric fields in tissue repair, and hypothesize that endogenous electric fields become part of stem cell niche in the wound site.

Keywords

stem cell / stem cell niche / electric field / tissue repair

Introduction

Cell-based therapy is one of the recent approaches in regenerative medicine that aims at replacing or repairing organs and tissues. Stem cells play an important role in tissue homeostasis and tissue repair throughout life. Different kinds of adult stem cells have been discovered during recent years, including mesenchymal stem cells, cardiac stem cells, renal stem cells, hepatic progenitor cells, muscle stem cells and so on.

It is known that endogenous stem cells reside in certain parts of virtually all organs, which is known as “stem cell niche”. Stem cell niche was originally recognized as a specific anatomic location that regulated stem cell self-renewal and differentiation [1]. During tissue repair, endogenous tissue stem cells actively participate in the healing process, while stem cell niches play important roles in this process. Besides, endogenous direect current electric fields (EFs) have also been proved to be a guiding cue for wound healing and tissue repair. Endogenous wound EFs were determined first more than 150 years ago by the German physiologist Emil Du-Bois Reymond, who measured ~1µA flowing out of a cut he made in his own finger, using a galvanometer(built with>2 miles of wire). Disruption of an epithelial layer instantaneously generates an endogenous EF, which has been proposed to be important in wound healing [2,3].

This review will briefly summarize stem cells niches in different tissues and organs and discuss the role of stem cell niches and endogenous electric fields in tissue repair.

Stem cell niche

Stem cell niche refers to an anatomical and functional structure, including cellular and extracellular components, local and systemic factors that are integrated to regulate stem cell proliferation, differentiation, survival and localization [4-6].In 1978, Schofield proposed the concept of “stem cell niche” in studies of the hematopoietic stem cells (HSCs) [7]. Since then, this hypothesis has been validated by a number of studies. The in vivo evidence of the existence of stem cell niche was first provided in studies using invertebrate models [8] and in the Drosophila germline stem cells [9,10]. In mammals, stem cell niches have been identified in different tissues over the past several years, including bone marrow, brain, hair follicles, intestines, and teeth [1,11-16]. Theoretically, a stem cell niche is composed of the stem cells themselves; stromal support cells; extra cellular matrix proteins; blood vessels and neural inputs [5], as is shown in Fig. 1. Recent studies have shown that oxygen may also be a critical component of stem cell niches, based on the fact that the undifferentiated states, proliferation ability and cell-fate commitment of embryonic, hematopoietic, mesenchymal, and neural stem cells were strongly influenced by low oxygen tensions (hypoxia) [17].

Skin stem cell niche

Studies have indicated that there are two stem cell niches in the skin, the hair follicle and interfollicular epidermis [18]. The hair follicle stem cells locate in the outer root sheath called the bulge, and are responsible for the regeneration of hair and sebaceous glands [19]. Label-retaining cells that mark the skin stem cell niche are constantly found in the bulge area [11], and cells isolated from bulge region can form large clones during in vitro culture [20,21].What’s more, lineage tracking experiments have also demonstrated that the bulge is the origin of cells in the lower follicle [22].The other stem cell niche in the skin is the interfollicular epidermis, and epidermal stem cells from this site normally give rise to stratified skin layers.

Neural stem cell niche

It has been reported that there are two neural stem cell (NSC) niches in the adult brain, which enable continuous generation of new neurons. The first NSC niche is the subventricular zone (SVZ) [23], which is a four to five cell diameter thick layer residing within the lateral walls of the lateral ventricles. Neural progenitors from SVZ function as the most important source of adult neurogenesis, which migrated through the rostral migratory stream to the olfactory bulb, and then differentiate into different interneuron subtypes [24,25].

The second NSC niche is the subgranular zone (SGZ), and progenitors from SGZ migrated to the granule cell layer and differentiate into granular neurons [26].

Renal stem cell niche

Several parts in the kidney have been identified as stem cell niches. It is reported in a recent study that the renal capsule may function as a novel stem cell niche [27]. Renal capsule derived cells showed self-renewal ability, clonogenicity and multipotency. Using in situ labeling of renal capsules with CM-DiI Cell Tracker, researchers have found that renal capsular cells contribute to nearly 25%-30% of the recovery from ischemia, and this result suggests a role for renal capsule as a functional stem cell niche [27]. Another area in the kidney, corticomedullary junction (CMJ), was also proposed as a renal stem cell niche, based on the findings that label-retaining cells were concentrated constantly in the outer stripe of the CMJ [28], and cultured cells from human CMJ showed strong clonogenicity and multipotency, which can differentiate into tubular cells, as well as glomerular podocytes [28].

Cardiac stem cell niche

Stem cell niches have been identified in the normal human myocardium. Human cardiac stem cells (hCSCs) divide symmetrically and asymmetrically within the niche, giving rise to differentiating and lineage-negative cells [29]. Clusters of hCSCs are connected by gap junctions and adherens junctions to myocytes and fibroblasts, which represent the supporting cells within the cardiac niches [30]

Stem cell niche and tissue repair

Stem cell niche represents a complex and dynamic entity in which multiple inputs are integrated to accomplish exquisite control of stem cell activities. There is increasing evidence that stem cell niche may play an important part in wound healing and tissue repair through regulation of local stem cell behaviors. One good example is the HSC niche. In adult bone marrow tissue, there are two HSC niches, osteoblastic niche, which serve as a reservoir for HSC storage [31-33] and vascular niche, which provides an environment for HSC proliferation and differentiation [33,34]. Reconstitution of the hematopoietic system after Injury is dependent on cooperation between the two niches [35].

In other organs, specific stem cell niches may also respond dynamically to regenerative cues and then exhibit substantial physiological alterations that affect how they interact with the stem cells to help restore tissue homeostasis. However, how the niche exactly effects the regulated conversion from homeostatic to regenerative modes of stem cell maintenance and self renewal is still unclear.

Endogenous electric fields and tissue repair

Naturally occurring EFs are an intrinsic property of wounds. Polarized epithelia transport ions directionally and maintain trans-epithelial potentials (TEP), which provide the basis of endogenous EFs. At skin and corneal wounds, injury disrupts the epithelial layer, short-circuits the TEP, and drive electric current flow (the positive charge flow) towards the wound from the surrounding tissues and then out from the wound [36,37], as is shown in Fig. 1. This wound-induced electrical signal was as large as 42-150 mV/mm, detected by microneedle arrays and Bio-Electric Imager® [38,39]. Furthermore, it could last for many hours and regulate different cell behaviors within 500 µm to 1 mm from the wound edge until reepithelialization occurres [40].

The TEPs are present in many other types of epithelia, in respiratory, gastrointestinal, urinary, and bile duct systems, as well as in prostate, breast, cerebral cavities, retina, and ocular lens [41].It is highly likely that in those epithelia the principles of wound EF generation and cellular responses are similar to those described for corneal and skin epithelium.

In the last decade, studies combining molecular, genetic and imaging techniques have provided convincing evidence that EFs play an important role in wound healing [14,36]. Significantly, this role may be far more important than expected because they override other directional cues in guiding cell migration in wound healing [15]. Song et al. [42] has found that closure of wounds in rat cornea is controlled by naturally occurring wound-induced electrical signals and disruption of these EFs using pharmacological tools disrupts wound healing. They found that the healing of rat cornea was inhibited with ouabain or furosemide, which decreased wound-induced electrical signal. On the contrast, the found that aminophylline or AgNO3 enhanced the wound-induced EFs and significantly accelerated the healing rate. Studies indicated that the mechanisms of EF-regulated wound healing included directional cell migration towards the wound edge, directional angiogenesis and regulation of cell proliferation and the axis of cell division [40,41].

In several recent studies, it has been reported that direct current electric fields exert significant effects on adult stem cell biology. Li et al. [40] showed that direct current EFs could induce directional migration of neural stem cells (NSCs) in vitro. They found that under EF stimulation, Nmethyl-D-aspartate receptors (NMDARs) in these cells were activated, which resulted in an increase in physical association of these channels with the Rac1 activator Tiam1 and effector Pak1, and then an enhancement of association with actin cytoskeleton, suggesting that NMDAR may act as a membrane transducer to transduce the extracellular EF stimulation to the intracellular Tiam1/Rac1/Pak1/actin pathway and thus play a role in directional NSC migration. Arocena et al. [43] reported that EFs suppressed the formation of protrusions of NSCs oriented toward the anode, while enhanced formation of protrusions towards the cathode, resulting in directed migration of NSCs towards the cathode.

Besides migration direction, EFs have also been reported to have effects on NSC differentiation. A recent study has found that NSCs aligned perpendicularly to the EF direction under EF stimulation and had a greater tendency to differentiate into neurons, but not into oligodendrocytes or astrocytes [44].

Under direct current electric fields, mesenchymal stem cells migrated toward the cathode in a dose-dependent manner [45], and reoriented perpendicular to the EF direction [46,47]. Our team has also found that human umbilical cord mesenchymal stem cells reorient perpendicularly to EF direction under an EF field, as is shown in Fig. 2. It has been reported that the cardiac differentiation of human embryonic stems was enhanced by electrical stimulation, and the mechanisms was associated with the intracellular generation of reactive oxygen species [48].However, it is unknown whether wound-induced EFs could affect stem cell biology in vivo. More studies are needed to uncover the role of EFs on other kinds of adult stem cells which also participate in the wound repair process, and to confirm those results in vivo in animal models.

Summary

Given the role of stem cells, stem cell niches and endogenous electric fields in wound repair of multiple tissues, we hypothesize that endogenous electric fields may be a critical, manipulable component of stem cell niche in the wound site, and may exert significant biological effects on local stem cells. The basis of this hypothesis are listed below: (1) as stated before, the definition of “stem cell niche” is a functional structure which includs all cellular and extracellular components that affect the stem cell biology. So if the migration of stem cells in the wound site can be controled by EFs, then the EFs should be considered as a part pf stem cell niche; (2) it is highly possible that endogenous wound EFs exert effects on local stem cells. EFs are generated when the epithelial layer is cut, and could last for many hours with a broad range, while various types of stem cells could be recruited to the site of wound injury, thus esterblishing a spatial and time relationship between EFs and stem cells at the wound site, as is shown in Fig. 1; (3) Several studies have proved that EFs could direct migration of stem cells in vitro, as stated before, so it is likely that stem cell migration is controled in vivo by local wound EFs.

Understanding the role of endogenous electric fields on stem cells and stem cell niches where a wound occurs will be quite valuable. Clinically, manipulation of the electric fields is a new and exciting avenue to pursue better wound healing and regeneration. New therapeutic strategies combining stem cells and manipulation of EFs may be developed, which will hold great promise for the regenerative medicine.

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