Clinical applications of mesenchymal stem cells | Journal of …

Journal of Hematology & Oncology20125:19

DOI: 10.1186/1756-8722-5-19

Wang et al.; licensee BioMed Central Ltd.2012

Received: 30January2012

Accepted: 16February2012

Published: 30April2012

Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside.

The online version of this article (doi:10.1186/1756-8722-5-19) contains supplementary material, which is available to authorized users.

Stem cells have the capacity to self-renew and to give rise to cells of various lineages. Thus, they represent an important paradigm of cell-based therapy for a variety of diseases. Broadly speaking, there are two main types of stem cells, embryonic and non-embryonic. Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocyst and can differentiate into cells of all three germ layers. However teratoma formation and ethical controversy hamper their research and clinical application. On the other hand, non-embryonic stem cells, mostly adult stem cells, 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. Recently, another type of non-embryonic stem cells, known as induced pluripotent stem cell (iPSC) has emerged as a major breakthrough in regenerative biology. They are generated through enforced expression of defined transcription factors, which reset the fate of somatic cells to an embryonic stem-cell-like state.

Cellular therapy has evolved quickly over the last decade both at the level of in vitro and in vivo preclinical research and in clinical trials. Embryonic stem cells and non-embryonic stem cells have all been explored as potential therapeutic strategies for a number of diseases. One type of adult stem cells, mesenchymal stem cells, has generated a great amount of interest in the field of regenerative medicine due to their unique biological properties. MSCs were first discovered in 1968 by Friedenstein as an adherent fibroblast-like population in the bone marrow capable of differentiating into bone [

]. It was subsequently shown that MSCs can be isolated from various tissues such as adipose tissue, peripheral blood, umbilical cord and placenta. These cells have a remarkable capacity of extensive in vitro expansion which allows them to rapidly reach the desired number for in vivo therapy [

]. Different laboratories have identified, under partly different isolation or culture conditions, MSCs with specific properties. For better characterization of MSC, in 2006, the International Society of Cellular Therapy defined MSCs by the following three criteria [

]:

MSCs must be adherent to plastic under standard tissue culture conditions;

MSCs must express certain cell surface markers such as CD73, CD90, and CD105, and lack expression of other markers including CD45, CD34, CD14, or CD11b, CD79alpha or CD19 and HLA-DR surface molecules;

MSCs must have the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts under in vitro conditions.

This review will provide an overview of the recent clinical findings related to MSCs. Roles of MSCs in clinical trials conducted to treat GVHD and cardiovascular diseases are highlighted. The therapeutic effects of MSC are mainly attributed to their four important biological properties. Here, we will discuss these four properties and the issues surrounding use of MSCs that need to be addressed during the transition of MSCs therapy from bench side to bedside.

While accumulating data have shown the therapeutic effects of MSCs in animal models of various diseases, we only focus on the clinical application of MSCs in this review. The first clinical trial using culture-expanded MSCs was carried out in 1995 and 15 patients became the recipients of the autologous cells [

]. Since then, a number of clinical trials have been conducted to test the feasibility and efficacy of MSCs therapy. By 2011/12/12, the public clinical trials database

has showed 206 clinical trials using MSCs for a very wide range of therapeutic applications Figure

). Most of these trials are in Phase I (safety studies), Phase II (proof of concept for efficacy in human patients), or a mixture of PhaseI/II studies. Only a small number of these trials are in Phase III (comparing a newer treatment to the standard or best known treatment) or Phase II /III (Figure

). In general, MSCs appear to be well-tolerated, with most trials reporting lack of adverse effects in the medium term, although a few showed mild and transient peri-injection effects [

]. In addition, many completed clinical trials have demonstrated the efficacy of MSC infusion for diseases including acute myocardial ischemia (AMI), stroke, liver cirrhosis, amyotrophic lateral sclerosis (ALS) and GVHD.

Clinical trials of MSCs are classified by disease types.

Clinical trials of MSCs are classified by phase.

Acute graft-versus-host disease (aGVHD) occurs after allogeneic hematopoietic stem cell transplant and is associated with high morbidity and mortality [

]. Currently, corticosteroids are the gold standard for initial treatment of aGVHD. However, they are only effective for some patients. Over the past decade, the immunomodulatory functions of MSCs have triggered great interests in their application for GVHD. Le Blanc K et al were the first to transplant haploidentical MSCs in a 9year old boy with severe treatment-resistant grade IV aGVHD of the gut and liver. They found the clinical response was striking and the patient was well after 1year [

]. A subsequent study was reported by Ringdn O et al in 2006. They gave MSC to eight patients with steroid-refractory grades III-IV GV
HD and one who had extensive chronic GVHD. Acute GVHD disappeared completely in six of eight patients. Complete resolution was seen in gut (6), liver (1) and skin (1). Their survival rate was significantly better than that of 16 control patients. Five patients are still alive between 2months and 3years after the transplantation [

]. The beneficial effect of MSCs infusion was then observed in a series of studies (Table

) .

A summary of the clinical experience of MSCs in GVHD treatment

2007 [11]

6

haplo-identical family donors (n=2), unrelated mismatched donors (n=4)

1.0x10(6)/kg

Acute GVHD disappeared completely in five of six patients, four of whom are alive after a median follow-up of 40months (range, 1890months) after the initiation of AMSC therapy. All four surviving patients are in good clinical condition and in remission of their hematological malignancy.

2008 [12]

55

HLA-identical sibling donors (n=5), haploidentical donors (n=18), third-party HLA-mismatched donors (n=69).

1.4x10 (6) (min-max range 0.4-9x10 (6)) cells per kg

30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1year after infusion than did patients with partial or no response

2008 [13]

7

hematopoietic stem cell donors (n=5), third party parental donor (n=2)

From 0.4x10(6) to 3.0x10(6) per kg based on availability

One out of three patients showed slight improvement of chronic GVHD. Two patients with severe acute GVHD did not progress to cGVHD. One patient received MSC to stabilize graft function after secondary haploidentical transplantation. One patient recovered from trilineage failure due to severe hemophagocytosis.

2009[14]

13

Unrelated HLA disparate donors

A median dosage of 0.9 x 10(6)/kg (range 0.6-1.1).

Two patients (15%) responded and did not require any further escalation of immunosuppressive therapy. Eleven patients received additional salvage immunosuppressive therapy concomitant to further MSC transfusions, and after 28days, five of them (45%) showed a response. Four patients (31%) are alive after a median follow-up of 257days, including one patient who initially responded to MSC treatment.

2009 [15]

33

PBSCT combined with MSCs

From 0.5x10 (5) to 1.7x10(6) per kg

Fifteen patients (45.5%) developed grade IIV acute GVHD (aGVHD) and only 2 (6.1%) developed grade III to IVaGVHD. Nine (31%) of 29 evaluable patients experienced chronic

GVHD (cGVHD).

2009 [16]

32

Unrelated, unmatched donor

2 or 8 million MSCs/kg in combination with corticosteroids

Ninety-four percent of patients had an initial response (77% complete response and 16% partial response). No infusional toxicities or ectopic tissue formations were reported.

2010 [17]

11

Unrelated HLA disparate donors

Median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg).

Overall response was 71.4%, with complete response in 23.8% of cases. None patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5months after infusion. Two patients developed chronic limited GVHD.

2011 [18]

12

premanufactured, universal donor

8 x 10(6)cells/kg in 2 patients and 2 x 10(6)cells/kg in the rest

7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. The cumulative incidence of survival at 100days from the initiation of therapy was 58%.

All these studies with varying numbers of patients and different degrees of GVHD severity suggest that complete and partial responses can be achieved in a majority of patients after MSCs infusion and that MSCs might represent a potential novel therapy for GVHD.

Despite progression of treatment options, ischemic heart disease and congestive heart failure remain major causes of morbidity and mortality. Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Among the used cell types, MSCs are an attractive candidate for cardiovascular repair due to their abovementioned biological properties. In preclinical studies using experimental animal models of cardiac injury, MSCs had been show to engraft after systemic or local administration and improve the repair of infarcted myocardium [1921]. In a rat model of dilated cardiomyopathy, Nagaya N et al found that MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium, resulting in decreased left ventricular end-diastolic pressureand increased left ventricular maximum [21].

Clinical trials using MSCs to improve cardiac function have also demonstrated encouraging results. For instance, in a pilot study, sixty-nine patients who underwent primary percutaneous coronary intervention within 12 hours after onset of acute myocardial infarction were randomized to receive intracoronary injection of autologous bone marrow mesenchymal stem cell or standard saline. Several imagining techniques demonstrated that MSCs significantly improved left ventricular function [22]. We conducted a clinical trial which recruited
sixty-nine patients with acute myocardial infarction after percutaneous coronary intervention (PCI). They were randomly divided into intracoronary injection of MSCs (n=34) and saline (n=35) groups. Three months after MSC transplantation, left ventricular ejection fraction (LVEF) in MSCs group increased significantly compared with that of pre-implantation and that of the control group [23].

Here we summarized the currently completed clinical trials registered with clinicaltrials.gov that using MSC to treat cardiovascular diseases (Table

). While a number of studies demonstrated the therapeutic effects of MSC transplantation, the underlying mechanisms remain unclear. The beneficial effects of MSCs might be mediated not only by their differentiation into cardiomyocytes but also by their ability to secret large amounts of bioactive molecules.

Completed clinical trials at present time with MSC expanded in vitro (http: //clinic altrials.gov)

Myocardial Ischemia

31

Autologous MSC from bone marrow

intramyocardial injections

Phase I/II

Non-randomized, Single group assignment, Open label

NCT00260338

Acute Myocardial Infarction

80

Autologous MSC from bone marrow

intracoronary injection

Phase II/ III

Randomized, Parallel assignment, Open Label

NCT01392105

Ischemic Heart Disease

48

MSC from bone marrow

intracoronary injection

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