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Current Stem Cell Reports

, Volume 4, Issue 4, pp 327–337 | Cite as

Mini Review: Application of Human Mesenchymal Stem Cells in Gene and Stem Cells Therapy Era

  • Ruixia Deng
  • Anna Hing Yee Law
  • Jiangang Shen
  • Godfrey Chi-Fung ChanEmail author
Genome Editing (SN Waddington and HC O'Neill, Section Editors)
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Part of the following topical collections:
  1. Topical Collection on Genome Editing

Abstract

Purpose of Review

Mesenchymal stem cells (MSCs) have abilities of self-renewal and multi-lineage differentiation. MSCs can evade immune rejection following allogeneic transplantation setting due to their downregulation of HLA Class II antigen. Therefore, we review the current understanding of using MSCs or MSC-conditioned media as treatment for various diseases.

Recent Findings

(1) MSCs regulate the balance of Th17/Treg cells in autoimmune disease models, which is associated with complex interactions among different pro- or anti-inflammation cytokines. (2) With the nature of MSCs migrating to multiple tissues under various homing signals, we also found MSCs are widely used as cell vehicles for gene or chemokine delivery.

Summary

MSCs or MSC-conditioned media therapies have been explored with advanced techniques. However, it still requires further investigations on (1) how MSCs respond to various microenvironments and (2) how to isolate, purify and expand enough MSCs ex vivo.

Keywords

Mesenchymal stem cells Cell therapy Autoimmune Paracrine Genetic modification Delivery tool 

Introduction

In 1968, mesenchymal stem cells (MSCs) were first derived, by Friedenstein et al., from bone marrow [1]. MSCs are historically considered as hematopoietic supporting cells that secrete growth factors and relevant cytokines. They are self-renewing multipotent progenitor cells with the potential to differentiate into cells of mesodermal origin, such as osteoblasts, adipocytes, and chondroblasts under standardized in vitro conditions. MSCs are plastic-adherent cells that express specific cell-surface molecules CD105+, CD73+, and CD90+ and do not express CD11b-, CD79a-, CD19- or human leukocyte antigen (HLADR-) [2]. They have been applied clinically for tissue repair and immune modulation in both pre-clinical and clinical studies due to their differentiation and immunosuppressive effects [3, 4, 5, 6] (Fig. 1). Here, we have summarized recent clinical translational studies of MSCs in two parts: (i) the application of primary MSCs as direct cellular therapy and (ii) the use of genetic modified MSCs as vehicles for gene therapy.
Fig. 1

The schematic diagram of roles of MSCs in direct and indirect applications. MSCs can be directly applied to inflammatory microenvironments, especially the Treg/Th17 modulated autoimmune diseases via either cell to cell responses or paracrine effects. On the other hand, MSCs can also be used as a vehicle to deliver therapeutic proteins in treatments for MS, HD, and cancer. MSCs mesenchymal stem cells, Treg T regulatory cells, Th17 T helper 17 cells, MS multiple sclerosis, HD Huntington’s disease

Part I

Applications of Primary MSCs

MSCs play an important role in immune regulation. They modulate functions of a wide spectrum of immune cells including lymphocytes, dendritic cells and natural killer cells. They exert their role both by direct contact and by secretion of anti-inflammatory soluble factors mostly via extracellular vesicles. To examine the immune suppression mechanisms of MSCs, we have studied various in vivo models, including graft versus host disease [7], murine collagen-induced arthritis [8] and bleomycin-induced pulmonary fibrosis in humanized mice [9••]. Researchers have been investigating the possibility of using MSCs as a biological drug to treat diseases including autoimmune diseases and neurodegenerative diseases, due to their immune-suppressive and regenerative potential. Our group has conducted clinical trials (IRB: UW 13-154) to investigate the therapeutic effects of MSCs for the treatment of graft versus host disease (GVHD) and the underlying mechanisms of suppressing the secretion of RANTES, CCL3, CXCL9, CCR5 and CXCR3 after 6 days after T cell transplantation in GVHD mouse model [7]. Immune-suppression effect of MSCs can also reduce the organ damages and inflammations in autoimmune diseases with unclear causes, a condition in which the immune system mistakenly attacks the owner’s body. MSCs act as therapeutic cells for autoimmune diseases, such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). Here, we addressed the updated applications of MSCs on patients or mouse models of SLE, MS and IBD [10].

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an incurable multi-organ systemic autoimmune disorder. Research has been carried out to investigate the underlying therapeutic mechanisms of MSCs in refractory SLE patients. A clinical study using allogeneic donor MSC transplantation to treat 30 patients with active refractory SLE showed they can balance the interaction between T regulatory (Treg) and Th17 cells. Upon infusion of MSCs, Treg cells were upregulated, while Th17 cells were suppressed; the processes were mediated through the secretion of transforming growth factor beta (TGF-β) and prostaglandin E2 (PGE2) [10]. In another study by Chen et al., MSCs increased the level of Treg cells in SLE patients, partly through soluble human leukocyte antigen sHLA-G [11]. On the other hand, by transferring functional mitochondria, MSCs also downregulated autophagy and apoptosis in T cells from SLE patients [12]. In a mouse model of SLE, CCL2 from transplanted MSCs was found to play a role in suppressing autoreactive T cells. CCL2 enhances T cell VCAM-1 expression and maintains cellular contacts, inhibiting IFN-γ production in turn [13].

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic disease that causes prolonged inflammation in the gastrointestinal tract. Systemic infusion of MSCs ameliorated the severity of colitis in a trinitrobenzene sulfonic acid-induced colitis mouse model, through suppressing inflammatory factors including IL-2, TNF-α, IFN-γ, T-bet, IL-6, IL-17, RORγt, and Th1-Th17-driven autoimmune responses [14]. While, in dextran sulfate sodium-induced IBD models [15, 16•], injection of MSCs increased the expression of IL-10 but suppressed the inflammatory cytokines including TNF-α, IL-6, IL-1β, IP-10, MCP-1, IFN-γ and also 15-LOX-1 [15]. Reductions of macrophage and dendritic cell infiltration in the intestinal lamina propria upon MSC treatment were also demonstrated [16•].

In order to further improve the therapeutic efficacy of MSCs in IBD, preconditioning of MSCs with Toll-like receptor (TLR-3) priming effectively improved clinical parameters and decreased pathological severity in colitis mouse models [17, 18]. The therapeutic enhancing effects were found to be mediated through the TLR3-activated Notch-1 signaling pathway [17].

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system in which the myelin sheath is damaged, leading to dysfunction of the brain and spinal cord. MSCs from different sources have been demonstrated to have immune modulatory functions and alleviate the symptoms in experimental autoimmune encephalomyelitis (EAE) mouse model [19, 20, 21•].

In delineating the mechanisms involved under MSC treatment, Anderson et al. showed that MSCs alleviated the disease severity by suppressing both the autoantigen-specific T cells and dendritic cells in EAE mice [22]. Tafreshi et al. showed that MSCs maintained the inactive form of GSK3-β in neurons, which ameliorated the symptoms in EAE mice [23].

Several studies were carried out aiming to improve the efficacy of MSC treatment in MS. Dang et al., which showed that autophagy is involved in regulating the therapeutic effect of MSCs in EAE mice and inhibition of the autophagy pathway by knocking down Beclin-1 significantly improved the treatment outcome through upregulating the immunosuppressive effect of MSCs [24•]. Treating MSCs with the small molecule resveratrol augments the therapeutic efficacy of MSCs in EAE mice. This treatment suppresses pro-inflammatory cytokines including IFN-γ and TNF-α and increases anti-inflammatory cytokines IL-4 and IL-10 [25]. Combination therapy of MSCs and nicotine significantly reduced the cumulative disease disability, which could be attributed to the reduced IL-17 and TNF-α levels [26].

Cell-Free Therapeutic Alternative

Instead of using the MSCs directly, recent studies have demonstrated that soluble factors and extracellular vesicles from MSCs may have similar therapeutic potential particularly for their immunomodulatory properties. Preclinical studies have been carried out to test the therapeutic effects of the secreted factors from MSCs in various disease models.

Conditioned medium from hypoxia-conditioned adipose-derived MSCs significantly accelerated wound healing by suppressing inflammation and promoting neovascularization and re-epithelialization in a gastric mucosal injury mouse model [27]. In an in vivo EAE experiment, it was shown that skin-derived MSCs produced soluble TNF receptor 1, which antagonized TNF-α and in turn suppressed Th17 cell differentiation. This action ameliorated the development of EAE in mice [28]. In a mouse model of thioacetamide-induced acute liver injury, although overall survival rate of the mice was not improved, conditioned-media from bone marrow-derived MSCs and embryonic stem cell-derived MSCs improved the biochemical and histopathological parameters of the injured livers, which provided support to the therapeutic potential of MSC secretome in acute hepatic failure [29]. With application in allogeneic hematopoietic stem cell transplantation, extracellular vesicles released from MSCs reduced the manifestations of acute graft-versus-host disease and the associated histologic changes. Further investigation showed that the frequencies and absolute numbers of CD3+CD8+ T cells, serum levels of IL-2, TNF-α, and IFN-γ were lowered, but serum IL-10 level was increased [30]. Systemic administration of MSC exosomes into rats with spinal cord injury significantly reduced lesion size and improved functional recovery. These protective effects were found to be mediated through reducing the pro-apoptotic and pro-inflammatory factors and upregulating the anti-apoptotic and anti-inflammatory proteins [31].

Part II

Genetic Modification of Mesenchymal Stem/Stromal Cells

With the advancement in biotechnology, scientists and clinical researchers are exploring new applications of genetically modified MSCs. Theoretically, after genetic engineering, MSCs should maintain most of their intrinsic properties with the addition of new functions, such as overexpression of specific proteins. It facilitates cell regeneration, tissue repair, cancer treatment, and immune modulation according to the genetic design. We summarized the recent published works in Table 1.
Table 1

Summary of genetic modifications of MSCs

Target tissue

MSC source

Modification Vehicle

Modified Gene

Brief Description

In vivo / in vitro

Reference(s)

Bone

Human

A nanocarrier of bioactive glass

BMP-2

Increased deposition of mineralized extracellular matrix

In vitro

[32]

Lentivirus

NELL1

Enhanced osteogenic differentiation

In vitro

[33]

Diabetes

Mouse

Adenovirus

SOD2

Reduced inflammation and improves glucose tolerance in vivo

In vivo: obese diabetic mice

[34]

Hemophilia

Mouse

Retrovirus

Human FVIII

hFVIII protein or activity is undetectable in plasma but induced immune tolerance to hFVIII

In vivo: Hemophilia A/immunocompetent mice

[35]

Mouse

Retrovirus

Porcine FVIII

High expression of porcine FVIII

In vitro

[36]

Mouse

Retrovirus

Porcine FVIII

High expression of porcine FVIII ex vivo; In vivo: porcine FVIII from modified MSCs rapidly neutralized but sustained high level porcine FVIII from modified HSC

In vivo: Hemophilia A/immunocompetent mice

[37]

Heart

Human

Lentivirus

HCN1

Created cardiac pacemaker cells

In vitro

[38]

Rat

Lentivirus

Hsp27

MSC survival in the infarcted heart

In vivo: rat myocardial infarction (MI)

[39]

Human

Lentivirus

HIF-1α

Improved components of the angiogenesis process under a hypoxic condition

In vitro

[40]

Human

Lentivirus

HCN2

Modify MSC to be cardiac pacemaker cells

In vitro

[41]

Rat

Lentivirus

Survivin (SVV)

Better prognosis for myocardial infarction (MI) by enhancing cellular survival

In vitro and In vivo(MI)

[42]

Rat

Adenovirus

Hsp20

Enhanced cell survival, revascularization, and functional improvement

In vitro and In vivo (MI)

[43]

Rat

FuGENE HD transfection reagent

Sonic Hedgehog (Shh)

Improved their survival and angiogenic potential in the ischemic heart

For in vivo studies, acute myocardial infarction model was developed in Fisher-344 rats.

[44, 45]

Rat

Lentivirus

hBcl-xL

Enhance survival rate of MSCs during transplantation

In vivo

[46]

Human

TALEN

TALEN-mediated AAVS1 site integration of VEGF

Precise site integration

In vivo: SCID mice; in rat myocardial infarction model

[47]

Ischemia

Human/mouse

Adenovirus

PGIS

Enhanced neovascularization in hind limb ischemia

In vivo: injection of these cells into ischemic muscles of unilateral hindlimb ischemia C57BL6/J mice

[48]

human

Nucleofection

Ephrin-B2

Promoted neovascularization in ischemic tissues

In vitro

[49]

Rat

Lentivirus

Overexpressing HIF-2a

RMSCs (HIF-2α) stimulated endothelial cell invasion under hypoxia; improves post-transplantation outcomes in a rat hindlimb ischemia model possibly by stimulating proangiogenic growth factors and cytokines

In vivo: a rat hindlimb ischemia model

[50]

Lung

Rat

Adenovirus

Transduced MSCs with HGF by adenoviral vector

Enhance tissue repair in acute lung injury rat model

In vivo: rat ischemia/reperfusion model

[51]

Neural disease

Mouse

Lentivirus

CRISPR/Cas9 and mutant HTT

CRISPR/Cas9-mediated editing of the mutation site of the Huntingtin gene (HTT) to silence it

In vitro

[52]

Rat

Lentivirus

GDNF

Attenuated neuropathic pain

In vivo: 4th lumbar and L5 DRGs of adult allogeneic rats

[53]

Mouse

Retrovirus

BDNF and/or NGF

Increase in neurogenesis-like activity

In vivo: YAC 128 transgenic mice

[54]

Human

Retrovirus

BDNF

Increase in neurogenesis-like activity

In vivo: immune-suppressed HD transgenic mice: YAC128 and R6/2.

[55••]

Human

Retrovirus

BDNF

Increase in neurogenesis-like activity

Plan to submit to FDA for clinical trial I

[56]

Mouse

Lentivirus

BDNF

Transdifferentiate into Schwann cells

In vitro

[57]

MSC

Human

Lentivirus

hTERT and VEGF

Prolonged life span and enhanced angiogenic ability

In vitro

[58]

Human

Lentivirus

NANOG and OCT4

Improved human bone marrow-MSC quality

In vitro

[59]

Cancer

Mouse

Retrovirus

CXCR4

MSCs migrated to injured and inflamed areas

In vivo: MDAMB231/Rluc tumor model

[60]

Human

Adenovirus

TRAIL-based TR3

MSCs migrated to tumor sites, triggering cancer cells apoptosis.

In vitro

[61]

Human

Adenovirus

Deletion of E1B19K gene or express TRAIL in oncolytic viruses

MSCs were applied as carrier cells for shielded virus delivery to tumors after ex vivo infection with oncolytic viruses

In vitro: Cancer cells

[62]

Human

Nucleofection

A single-chain antibody against EGFRvIII

Targeting of hMSCs to specific cell populations within tumors

In vitro

[63]

Human

Adenovirus

Apoptin

Induced hepatoma cell death

In vitro and In vivo (nude mice)

[64]

Mouse

Lentivirus

TNF-α and CD40L

Enhanced cancer therapy by triggering antitumour immune responses

In vivo: BALB/c mouse

[65]

Mouse

rAAV

IFN-β

MSC-based IFN-β therapy for prostate cancer lung metastasis

In vivo: immuno-competent mouse model of prostate cancer lung metastasis

[66]

Either naïve or genetically modified MSCs have been widely used in academic and clinical research for various indications. Primary human MSCs are precious and the expansion rate is slow with finite ex vivo life span. Therefore, human MSCs are engineered by expressing either hTERT to prolong the life span [58] or Nanog and Oct4 to improve stemness [59, 67].

At first, adenoviral, retroviral, and lipid vectors were used to engineer MSCs [35, 36, 68, 69, 70]. However, due to safety considerations, several non-viral transduction methods have been developed in recent years, including methods using nanoparticles, electroporation, and polymers (polyethylenimine) [71, 72, 73, 74]. A comparison between non-viral and viral vector methods on porcine MSCs shows that viral transduction has a higher efficiency but lower survival rate [75]. Besides optimizations of lentiviral vector and adeno-associated virus (AAV) methods, RNA viral vectors and new materials are increasingly popular in gene modification of MSCs [32, 76, 77, 78]. For examples, Sendai virus and a glass macromolecular carrier have been used in the past 5 years. There is a study using TALEN-genome editing to introduce the inducible VEGF gene cassette into a safe harbor genomic site of thuman umbilical cord blood-derived MSCs, resulting in enhanced angiogenesis in vivo [47]. Lenti-CRISPR/Cas9 gene editing of MSCs is also used for silencing the mutant Huntingtin gene [52]. A detailed discussion of various methodologies is outside the scope of this review but has been recently reviewed by Park [79••].

MSC as Delivery Vehicle in Immuno-Regulation

Owing to the unique homing ability of MSCs to many tissues, the therapeutic potential of using MSCs as delivery vehicle to treat various diseases, especially cancers, have been investigated. MSCs carrying an engineered suicide gene or drug-sensitive gene have been used in various cancer models, including pancreatic cancer [80], hepatocarcinoma [81], neuroblastoma [82], and brain metastatic melanomas [83]. On the other hand, with the immune tolerance property, MSCs have become a promising candidate in developing cell-based therapy. In a collagenase-induced osteoarthritis mouse model, MSCs overexpressing IL-10 were injected into the affected knee of the diseased mice and the results showed a significant reduction in activated CD4 and CD8 T cells resulting in reduced disease severity [84]. In a transient middle cerebral artery occlusion model, rats received MSCs overexpressing IL-10 after ischemia-reperfusion. This significantly reduced infarct volumes and improved motor function [85]. MSCs overexpressing IFN-β increased the Treg and IL-10 levels in EAE mice, while the IL-17 level was suppressed [86]. Neuroinflammation was also ameliorated in EAE mice when injected with IFN-β expressing MSCs [87]. While in another study, MSCs overexpressing IL-10 together with selectin ligands P-selectin glycoprotein ligand-1 (PSGL-1) and Sialyl-Lewisx (SLeX) were transplanted into EAE mice. MSCs homing to the inflamed spinal cord were significantly enhanced, and the therapeutic effect of the triple PSGL1/SLeX/IL-10 engineered MSCs was better than naïve MSCs [88].

Neurological Diseases

Brain-derived neurotrophic factor (BDNF), neurotrophin nerve growth factor (NGF) and Glial cell-derived neurotrophic factor (GDNF) are important for neuronal cells survival, maintenance and regeneration. These neurotrophic factors have been considered as potential therapeutics for neurodegeneration diseases, such as Parkinson’s, Alzheimer’s and Huntington’s diseases. Genetic modified MSCs are thought to be an ideal delivery tool for these therapeutic factors in neuro-repair [52, 55••, 56, 57, 89]. Isolated from either human donors, mice, or rats, MSCs can be programmed to heterogeneously secrete BDNF and/or NGF [55••, 56, 57] by using retroviral transduction. Those programmed MSCs can produce sustainable, effective specific growth factors and are capable of transdifferentiating into neuron-like cells, oligodendrocyte-like cells and Schwann cells in vitro. Huntington’s disease (HD) is caused by mutations in exon 1 of the huntingtin gene. Reduced BDNF expression due to the mutant huntingtin protein correlates with and is indicated to be the major cause for neurodegeneration in HD brain. MSCs engineered to secrete NGF or BDNF decreased striatal atrophy and reduced anxiety in HD transgenic YAC128 mice [54, 55••]. Currently, this approach has been submitted to FDA for a phase I clinical trial of MSC/BDNF in patients with HD [56]. Furthermore, MSC/BDNF is also considered for clinical studies of regeneration in traumatic brain injury, spinal cord, and peripheral nerve injury. MSCs transduced with GDNF can potentially attenuate neuropathic pain and inflammation in spinal cord injury models [53].

Tissue Repair and Regeneration

Ischemia heart disease (IHD) is the most common type of heart disease [90]. Preclinical studies of ischemic and non-ischemic cardiomyopathy employing MSC-based therapy have demonstrated MSCs’ properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis [91, 92, 93, 94]. However, low cell survival and engraftment rates have restricted MSC application in transplantations.

To achieve higher survival rate of transplanted MSCs, one approach is to directly overexpress proteins that promote cell survival, such as heat shock protein 27 (Hsp27) [39], heat shock protein 20 (Hsp20) [43], survivin (SVV) [42], and hBcl-xL [46] in MSCs before transplantation. Another method is to reduce hypoxia damage caused by ischemia. For example, genetic modification of MSCs by hypoxia-inducible factor 1 alpha (HIF-1α) overexpression improves the angiogenesis process under hypoxic condition [40]. Or alternatively, to increase oxygen delivery by enhancing angiogenesis, such as expressing vascular endothelial growth factor (VEGF) [47], and sonic hedgehog (Shh) [44, 45] in MSCs for delivery in vivo and in vitro. Overexpression of HIF-2α in MSCs stimulates endothelial cell invasion under hypoxia and improves blood perfusion and arteriogenesis [50]. MSCs with transduction of HIF-2α, prostacyclin synthase (PGIS) by adenoviral vector, or ephrin-B2 via nucleofection-enhanced neovascularization in hindlimb ischemia rat model [48, 49, 50].

Tissue damage often intensifies the inflammatory response. Hepatocyte growth factor (HGF) secreted by MSCs has immunosuppressive effects in vivo and in vitro [95]. Therefore, overexpressed HGF from MSCs can enhance tissue repair in an acute lung injury rat model [51] and skeletal muscle recovery in muscle injury model [51].

In proof-of-concept studies to develop substitutes for electronic pacemakers, MSCs were converted into cardiac pacemaker cells by transducing hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) [38] and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) [41] genes using lentiviral vectors.

Cancers

MSCs exist in many tissues and can migrate to various injury sites [96] including the tumor microenvironment. The tumor microenvironment is essential in supporting cancer cell growth including invasion, proliferation, and dissemination [97]. Numerous reports have described that MSCs are ambivalent to be either pro- or anti-tumorigenic. The roles of MSCs involved in the tumor microenvironment are complex and unclear. We have focused on how genetically modified MSCs can improve their capability in (i) migration to cancer cells [60, 63], (ii) triggering cancer cells death [61, 62, 64], and (iii) stimulating antitumor immune response [65, 66]. Another excellent review on the role of MSCs in cancer was written by Sage et al. [98].

Our group found that the interaction between SDF1 and its receptor CXCR4 plays an important role in migration of MSCs [99, 100]. MSCs genetically modified by retroviral transduction to overexpress CXCR4 improves MSC homing and migration to tumor sites [60, 101]. Another effort to enhance tumor-specific homing of MSCs is to express a transmembrane single-chain antibody against EGFRvIII a target protein on glioblastoma multiforme (GBM) cell surface [63]

Most conventional anti-cancer treatments aim to kill cancer cells mainly by targeting at rapidly proliferating cells. Such an approach is barely satisfactory because of significant off-target effects on healthy tissues or cells. With capability of migrating to tumor sites, we may induce MSCs as an anti-cancer armamentarium in cancer-associated microenvironment. Zhang et al. genetically modified MSCs to release adenoviral particles coding apoptin targeting hepatoma cells in vitro and in vivo [64]. Apoptin, a small protein from chicken anemia virus, resides in the cytoplasm of normal cells but translocates into the nucleus of cancer cells. There, it accumulates and triggers a p53-independent mitochondrial death. This study successfully utilizes MSCs as a novel in vivo drug delivery vehicle to the tumor site and inhibited tumor growth. With a similar idea, Hammer et al. engineered modified MSCs as carrier cells of adenoviruses to serve as oncolytic virus in vitro. In this study, they optimized adenoviral production from MSCs by deletion of the anti-apoptotic viral gene E1B19K or expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the engineered oncolytic adenoviruses (OAds) [62]. Adenovirus transduced MSCs secreting a TRAIL-based anti-cancer therapy showed benefit in MUC16-expressing ovarian cancer cells [61]. However, further investigations and evaluations in an in vivo tumor xenograft mouse model are required.

The immune system plays a key role in controlling cancer initiation and progression. Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. MSCs are continuously recruited to and become an integral component of the tumor microenvironment. Although the roles of MSCs in tumor remain elusive, they were modified to trigger antitumor immune responses by expressing TNF-α/CD40L [65] or IFN-β [66] for cancer therapy. These studies yielded satisfactory outcomes with increased antitumor immune response noted. Such approach also increased the experimental mice lifespan or decreased in vivo tumor volume.

Other Applications

In 1998, Evans and Morgan used a retroviral vector to transduce murine bone marrow with human coagulation factor VIII [35]. The method of retroviral vector-mediated gene transfer into hematopoietic progenitors in the mouse achieved > 30% efficiency. However, they did not identify the cell populations in the transduced murine bone marrow. Both hematopoietic progenitors and mesenchymal stromal cells were likely involved. This approach can serve as a promising tool for the delivery of secreted proteins. MSCs have been genetically modified to express clotting factor VIII using retroviral vectors [36, 37]. However, MSC-secreted factor VIII induced anti-factor VIII neutralizing antibodies quickly after transplantation in immunocompetent mice [37].

Since MSCs are also known as osteoblast progenitors, their applications in bone regeneration as drug and gene delivery carriers have been explored. Kim et al. developed a nanocarrier of bioactive glass loaded with genetic-modified MSCs overexpressing BMP2 [32]. An in vitro study shows that BMP2 was released in a sustained manner and subsequently, the rat MSCs expressed all bone-related genes within 2 weeks. Another recent study describes transduction of NEL-like protein 1 (NELL1) gene into human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) [33]. Mineral synthesis was increased by 81% in NELL1-iPSC-MSCs at 21 days in vitro. NELL1 overexpression can greatly enhance the osteogenic differentiation and mineral synthesis of iPSC-MSCs. However, due to the tumorigenesis risk of iPSCs, it is necessary to safe guard the purity of iPSC-MSCs before clinical application.

Conclusions and Perspectives

Based on the available MSC-related preclinical and clinical data, MSC-based therapies can be applied to a wide spectrum of clinical disorders. However, the nature of the illnesses and the specific targeted tissue for repair have to be pre-selected carefully and should be done under strict clinical trial setting. Use of MSCs as an adjunct to existing treatment regimen or utilization of genetically modified MSCs for specific protein delivery are attractive concepts but the actual clinical feasibility has to be investigated thoroughly. Some ongoing studies attempting to manipulate the genetic or epigenetic profile of MSCs for clinical application by using either chemicals or soluble factors are attractive ideas but remains to be proven. Galaderisi reviewed 493 MSC-based clinical trials in 2016. The top 3 fields are bone and cartilage disease (19.1%), neurological disease (17.8%), and cardiovascular diseases (14.8%) [102]. According to their records, promising therapeutic outcomes with recipient tolerability of MSC were observed in completed trials. However, recent studies also show both cancer-promoting and anticancer potentials of MSCs [103]. The role of MSCs in tumor progression and metastasis remains to be further investigated. For safe and effective therapy, questions remain as to the best MSCs to be used according to their sources, passage number, dosage, culture condition, etc. They have to be clarified in comparative studies. The current limitations of MSCs in clinical applications are their heterogeneity in the culture system and their finite ex vivo expansion capacity. The use of iPS cell-derived MSCs or immortalized MSCs are two possible solutions to overcome such limitations.

Notes

Acknowledgments

Many thanks to Dr. Hang Liu, Dr. Amy Bun Tsoi and Dr. Chong Gao for the assistance with the revisions. Works are supported by the donation from Providence Foundation Limited, Hong Kong.

Compliance with Ethical Standards

Conflict of Interest

Ruixia Deng, Anna Hing Yee Law, Jiangang Shen and Godfrey Chi-Fung Chan declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Ruixia Deng
    • 1
    • 2
  • Anna Hing Yee Law
    • 1
  • Jiangang Shen
    • 2
  • Godfrey Chi-Fung Chan
    • 1
    • 3
    Email author
  1. 1.Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, 7/F, Laboratory BuildingThe University of Hong KongPokfulamHong Kong
  2. 2.School of Chinese Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong
  3. 3.Department of Paediatrics and Adolescent MedicineQueen Mary HospitalHong KongHong Kong

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