Mesenchymal stem cells hold promise for regenerative medicine

Abstract

Regenerative medicine is an emerging interdisciplinary field of research that uses several technological approaches including stem cells to repair tissues. Mesenchymal stem cells (MSCs), a type of adult stem cell, have generated a great amount of interest over the past decade in this field. Numerous studies have explored the role of MSCs in tissue repair and modulation of allogeneic immune responses. The mechanisms through which MSCs exert their therapeutic potential rely on some key properties of the cells as follows: the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial, and neuronal cells; the ability to secrete multiple bioactive molecules capable of stimulating the recovery of injured cells and inhibiting inflammation; the lack of immunogenicity; and the ability to perform immunomodulatory functions. In the present review, we focus on these three aspects upon which the therapeutic effects of MSCs are mainly based. Furthermore, some pathological conditions under which the application of MSCs should be done with caution are also mentioned.

Keywords

mesenchymal stem cells / differentiation / immunomodulation / regenerative medicine

Introduction

Regenerative medicine is an emerging interdisciplinary field of research and clinical applications focused on the repair, replacement, or regeneration of cells, tissues, or organs to restore impaired function resulting from multiple causes, including congenital defects, disease, and trauma. Regenerative medicine uses a combination of several technological approaches that transcend beyond traditional transplantation and replacement therapies. These approaches include, but are not limited to, the use of stem cells [1]. Many different types of stem cells can be used for regenerative medicine, including the following: (1) Embryonic stem cells derived from the inner cell mass of the blastocyst, and can produce the entire repertoire of cells in the body. However, they form teratoma when transplanted directly, and they are ethically controversial. (2) Adult stem cells, which are already somewhat specialized and have limited differentiation potential. They can be isolated from various tissues and are currently the most commonly used seed cells in regenerative medicine. One example is hematopoietic stem cells (HSCs), which sustain blood formation throughout our entire lives and are restricted in their developmental potential to generate only blood cell lineages. Currently, HSC transplantation is a routine medical procedure for several diseases. (3) Induced pluripotent stem cells (iPS) are generated through nuclear reprogramming, which resets the fate of somatic cells to an embryonic stem cell-like state. iPS cells have normal karyotypes, express genes typical of ES cells, and maintain the developmental potential to differentiate into cells of all three germ layers. iPS cells are a major breakthrough in regenerative biology.

In the present review, we focus on mesenchymal stem cells (MSCs), a type of adult stem cell that has generated a great amount of interest as a potential therapy for various diseases. MSCs were first discovered in 1968 by Friedenstein et al. [2] as an adherent fibroblast-like population in the bone marrow capable of differentiating into bone. Since then, a similar population has been isolated from various tissues, such as adipose tissue, peripheral blood, umbilical cord, and amniotic fluid. Given a lack of unique MSC surface markers, the International Society of Cellular Therapy defined MSCs in 2006 based on three criteria as follows: (1) MSCs must be adherent to plastic under standard tissue culture conditions; (2) MSCs must express certain cell surface markers, such as CD73, CD90, and CD105, and lack the expression of other markers, including CD45, CD34, CD14, or CD11b, CD79alpha or CD19 and HLA-DR surface molecules; and (3) MSCs must have the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts under in vitro conditions [3]. These cells possess the following advantages: (1) they are easy to obtain and are highly proliferative under ex vivo culture conditions and (2) neither autologous nor allogeneic MSCs induce any immunoreactivity in the host upon local transplantation or systemic administration [4,5]. Our laboratory has been studying the biologic characteristics of MSCs, their therapeutic effects, and the underlying mechanisms for over a decade. We believe that the current enthusiasm surrounding the potential application of MSCs for therapeutic purposes is based on their multilineage differentiation capacity, their immunomodulatory properties, and their ability to secrete bioactive molecules. We illustrate these three aspects in detail, based on the experimental results obtained in the present review.

Therapeutic effect based on multilineage differentiation capacity

MSCs have the capacity to differentiate into mesenchymal lineages including osteoblasts, adipocytes, and chondroblasts under in vitro conditions [6]. We isolated MSC from a human fetal bone marrow, called Flk1⁺CD31^-CD34^- stem cells, and found that they could differentiate into the above mentioned lineages, and also into cells of the three germ layers, such as endothelial, hepatocyte-like, neural, and erythroid cells at the single-cell level [7,8]. Based on this finding, we hypothesized that post-embryonic subtotipotent stem cells exist [9], and this hypothesis was later confirmed by other scientists (Table 1).

MSCs have great differentiation potential, so they can be used to treat various diseases by replacing damaged cells. In our laboratory, we proved this application with a series of animal disease models. In a C57BL/6 mouse model of ischemia-reperfusion kidney, transplanted human adipose tissue-derived MSCs were able to differentiate toward renal tubular epithelium at an early stage of injury. The differentiated donor cells replaced the vacant space left by the dead cells, thereby contributing to the maintenance of structural integrity and proceeding to a subsequent tissue-repair process [17]. In Wistar rat models of diabetic retinopathy, transplanted MSCs differentiated into photoreceptor and glial-like cells in the retina, which improved the integrity of the blood-retinal barrier in diabetic rats [18]. In mdx mice, AD-MSCs homed on the injured muscle tissues and differentiated into myotubes and endothelial cells, as well as muscle satellite cells [19]. Other examples of the use of MSC to treat diseases through differentiation are shown in Table 2.

Therapeutic effect based on secretion of multiple bioactive molecules

MSCs do more than respond to stimuli and differentiate. Proteomic analyses of MSC-conditioned medium indicate that MSCs secrete many known growth factors, cytokines, and chemokines, which have profound effects on local cellular dynamics. Table 3 shows some important soluble factors secreted by MSC. Both in vitro and in vivo studies indicate that many cell types are responsive to MSC paracrine signaling. The effects of MSC-secreted bioactive molecules can be either direct or indirect or even both: direct by causing intracellular signaling or indirect by causing another cell in the microenvironment to secrete functionally active agent. The secretion of soluble factors is the mechanism underlying the therapeutic effect of MSC in many disease models.

Cerebral ischemia is a prime clinical neurologic disorder, and MSC transplantation in ischemic tissues could improve the neurologic functions by increasing interleukin-10 (IL-10) expression. IL-10 is a well-known anti-inflammatory cytokine with neuroprotective effects [35]. Previous studies suggest that MSCs have the ability to protect cultured neurons from excitotoxicity-induced apoptosis. We proved that MSC could be protective against glutamate-induced injury in PC12 cells, and this effect is mediated by secreted neurotrophic factors, including endothelial growth factor, hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor [36].

Therapeutic effect based on immunomodulatory functions of MSCs

MSCs lack immunogenicity because they express low levels of major histocompatibility complex-I (MHC-I) molecules and they do not express MHC-II molecules and costimulatory molecules, such as CD80, CD86, or CD40 [37]. This unique property allows for the transplantation of allogeneic MSCs. MSCs can also modulate the functions of the immune system by interacting with a wide range of immune cells, including T lymphocytes, B lymphocytes, natural killer cells, and dendritic cells. MSCs regulate the proliferation, activation, and maturation of T and B lymphocytes in vitro in a dose-dependent and time-limited manner [38,39], and they can facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-κB signaling [40]. We first reported that MSCs could inhibit the upregulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation [41]. We also demonstrated that in the presence of MSCs, the percentage of cells with cDC phenotype is significantly reduced, whereas the percentage of pDC increases, further suggesting that MSCs can significantly influence DC development [42]. MSCs could drive maDCs to differentiate into a novel Jagged-2-dependent regulatory DC population and escape their apoptotic fate, providing more evidence to support the role of MSCs in rejection prevention during organ transplantation and treatment of autoimmune disease [43]. We first reported the immunomodulatory effects of MSCs on the abnormal immune system of BXSB mice which were born with immunologic deficiency and developed lupus naturally. MSCs can significantly downregulate Th2 cells in pathological conditions and further inhibit the abnormal activation of humoral immunity to maintain the original balance [44]. MSCs lack immunogenicity and can modulate the immune system simultaneously. These two properties make them great candidates for applications in both the induction of tolerance in transplantation and in the treatment of autoimmune diseases. A report showed that cotransplantation of MSCs prevents death from graft-versus-host disease (GVHD) without abrogating the graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning [45]. We explored the efficacy and safety for treating chronic graft-versus-host disease (cGVHD), particularly sclerotic skin manifestations of cGVHD (ScGVHD) by MSC transplantation. Patients with ScGVHD had improved symptoms after receiving MSC expanded ex vivo from unrelated donors by intra-BM injection [46]. Based on studies in our laboratory, we drew a schematic picture of the immunomodulatory effects of MSCs both in vitro and in vivo (Fig. 1).

Possible side effects related to the application of MSCs

From the literature, MSCs possess a vast therapeutic capacity that assists in the treatment of various diseases. However, side effects related to MSC transplantation have also been reported. Karnoub et al. [47] co-injected bone marrow-derived human MSCs with green fluorescent protein-labeled human breast cancer cells MCF/Ras into immunocompromised mice, and found that MSCs accelerate breast tumor growth, as well as cancer metastases. We cultured two cancer cell lines (MDA-MB-435S and MCF7) with human adipose-derived MSCs, and found that the invasive capacity and migration ability of the two cancer cell lines post-coculture were significantly enhanced (unpublished data). To date, various reports emphasized the pro-tumor growth role of MSCs. In addition, MSCs could aggravate arthritis in a collagen-induced arthritis model by at least upregulating the secretion of IL-6, which favors Th17 differentiation [48]. These studies remind us that we should be cautious about subjects with some pathological conditions when using MSCs for patients.

Conclusions and future prospects

MSCs hold promise to fulfill unmet needs in regenerative medicine, and have recently emerged as great candidates for cell-based therapy because they can differentiate into a wide range of cells; produce a series of growth factors, cytokines, and signal molecules; as well as modulate the immune responses in various ways. Although we divided the effects of MSC into these three aspects for better description in the present review, in reality, these three aspects are combined and overlapped. For example, MSCs exert their immunomodulatory effect by secreting bioactive factors, such as IL-10. MSCs can differentiate into specific cell types and secret new bioactive factors in accordance with the microenviroment. Thus, these effects are not separated; instead, they interconnect with each other.

Although tremendous progress has been achieved by scientists and clinicians, future research in this field should continue and focus on elucidating some main issues. The first issue concerns the mechanisms underlying MSC multilineage differentiation. Lineage specification of MSCs is tightly controlled by both genetic and epigenetic factors. Recently, microRNAs, a class of non-coding RNA that regulates gene expression at the post-transcriptional level, have been demonstrated to play an important role in MSC differentiation. We found that microRNA-138 could inhibit adipogenic differentiation of human MSCs through EID-1 [49]. Genetic and epigenetic factors intertwine, further complicating the mechanisms governing MSC differentiation. The second issue concerns how MSCs react to the environment and secrete bioactive molecules accordingly. The third involves the mechanism underlying MSC immunomodulatory function. The last issue entails determining possible adverse effects and complications that might arise from MSC transplantation. We believe that eventually, a novel and safe therapy with MSCs can emerge and revolutionize treatment and therapies for patients with severe diseases.

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