Osteoarthritis and Cartilage

What is the rational for mesenchymal stromal cells based therapies
in the management of hemophilic arthropathies?

Alexandre Théron # † ‡, Marie Maumus #, Christine Biron-Andreani †, Nicolas Sirvent ‡, Christian Jorgensen # §, Danièle Noël # § *

# IRMB, University of Montpellier, INSERM, Montpellier, France
† Resources and Competence Center for Hereditary Hemorrhagic Diseases, CHU Montpellier, Montpellier, France
‡ Department of Pediatric Oncology and Hematology, CHU Montpellier, Montpellier, France
§ Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU Montpellier, Montpellier, France

article info

Article history:
Received 18 September 2023
Accepted 7 December 2023

Keywords:
Hemophilia
Hemophilic arthropathy
Mesenchymal stromal cell
Gene therapy
Cell therapy

SUMMARY

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients’ quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications.

Introduction

Hemophilia is an X-linked genetic bleeding disorder affecting approximately 1.2 million people worldwide. It is due to a deficiency in coagulation factors VIII (hemophilia A) or IX (hemophilia B).¹ Coagulation factors present in the blood work with platelet cells to form clots to stop the bleeding. The risk of bleeding is directly related to the factor level and therefore, severe hemophilia has a much higher risk of bleeding than moderate or minor forms. The mortality associated with hemophilia is mainly due to bleeding and neurological bleeding is the most severe complication together with hemarthrosis or joint bleeding. Successive hemarthroses ultimately lead to hemophilic arthropathy (HA), which is characterized by synovial inflammation, cartilage degradation and bone destruction with severe impact on the patient’s quality of life and significant functional repercussions.² To date, the main treatment for hemophilia remains preventive with the infusion of factor concentrate. The development of prophylactic treatments has made it possible to significantly reduce bleeding and thereby the complications of hemophilia.³ However, a number of patients experience severe joint damages for which no treatment is available and the last resort is orthopedic surgery with joint replacement or arthrodesis. New treatment modalities are therefore warranted. The objective of the review is to discuss new therapeutic approaches with a special focus on the few studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA.

* Correspondence to: Inserm U1183, IRMB, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France.
E-mail address: daniele.noel@inserm.fr (D. Noël).

Method

We conducted a systematic review of the literature between 1946 and August 31, 2023. We searched the MEDLINE database for articles associating the keywords “Mesenchymal stromal cell” or “Mesenchymal stem cell” combined with hemophilia. We then excluded reviews of the literature, articles not in English, articles dealing with cell types other than MSCs, method/technique articles and articles whose objective was not the use of MSCs as a treatment for stopping the bleedings or the complications of hemophilia (production of FVIII or FIX, treatment of arthropathy). In total, we found fifty-three articles in English and excluded ten literature reviews, thirteen articles using other cell sources, five purely technical articles and five articles that did not investigate
the properties of MSCs for the treatment of hemophilia bleeding complications.

Fig. 1

Main mechanisms involved in hemophilic arthropathy. ADAMTS: A
disintegrin and metalloproteinase with thrombospondin motifs; IL:
interleukin; MMP: metalloproteinase; RBC: red blood cells; ROS:
reactive oxygen species; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor.

Joint damage in hemophilia

Hemarthrosis is acute intra-articular bleeding, with or without trauma, which occurs as soon as the age of walking and affects more than half of severe hemophiliacs. Hemarthrosis preferentially affects, in the order of frequency, knees, elbows, ankles, hips and shoulders.4 The administration of coagulation factors, immobilization, and analgesics can resolve acute bleeding, but the risk of developing arthropathy exists from the first hemarthrosis.5 Nevertheless, severe HA generally results from recurrent hemarthroses. Intra-articular bleeding causes an acute increase in joint volume leading to the accumulation of blood components into the joint and triggers the lysis of red blood cells and the release of iron (Fig. 1).6–9 It takes about a week for the blood to be cleared from the joint cavity by the synovial cells but in recurrent bleedings, their capacity is overwhelmed resulting in iron deposition and initiation of a cascade of inflammatory and degrading activities.10 It results in chronic pain and functional impairment. In hemophiliacs, the joint is more vulnerable to bleeding because of the low levels of Tissue Factor (TF), the initiator of the coagulation cascade, while the level of TF pathway inhibitor is high. Moreover, the local fibrinolytic process is stimulated with increased production of plasmin and reduced generation of thrombin resulting in clot resolution.11 HA is characterized by acute synovial inflammation and hyperplasia, as seen in inflammatory joint diseases such as rheumatoid arthritis (RA) and, cartilage degeneration, which is also seen in degenerative joint diseases, such as osteoarthritis (OA). Synovial inflammation and hypertrophy result from synoviocyte proliferation, macrophage attraction into the joint and diffuse lymphocyte infiltration around hemosiderin deposits (Fig. 1). The accumulation of iron derived from erythrocytes plays a key role in these processes12

The inflamed synovial membrane produces pro-inflammatory cytokines such as interleukin-1β (IL1β), Tumor Necrosis Factor-α (TNFα), IL6 and reactive oxygen species (ROS), which activate the production of catabolic enzymes such as metalloproteinases (MMPs) and A Disintegrin And Metalloproteinase with Thrombospondin Motifs, thereby contributing to oxidative stress and cartilage degradation.^2,13–15 Another characteristic of HA is synovial neo-angiogenesis, which is triggered by pro-angiogenic factors such as vascular endothelial growth factor and stromal cell-derived factor1. ¹⁶ Those factors are stimulated by hypoxia-induced factor-1 α upregulation resulting from the high demand in oxygen caused by synovial proliferation and reduced blood flow upon increased intraarticular pressure.¹⁷ Subsequently, the inflamed and thickened synovium is more susceptible to mechanical damage and successive bleedings, which eventually lead to a fibrotic synovial tissue.
Cartilage degeneration occurs following blood exposure that directly and severely affects cartilage homeostasis demonstrated by the imbalance between matrix synthesis and degradation that can last up to ten weeks.2 Dysregulated cartilage turnover is primarily due to chondrocyte apoptosis resulting from iron-induced oxidative stress. As previously discussed, cartilage matrix degradation is also triggered by IL1β-induced production of MMPs and aggrecanases. In addition, the increased production of plasmin in joints upon blood exposure contributes to activation of these enzymes and cartilage degradation. Nevertheless, HA pathogenesis appears to be dominated by degenerative cartilage changes more than inflammationmediated damages.¹⁸
HA is also associated with bone changes including osteophyte formation, subchondral sclerosis, cyst formation, epiphyseal enlargement and osteoporosis. These changes result from a disequilibrium in bone formation and bone resorption processes induced by inflammation and leading to decreased bone mineral density and osteoporosis. In addition, reduced physical activity of hemophiliacs, as well as lower osteoblast proliferation due to decreased thrombin production may participate to higher bone resorption activity.

Current treatments for HA

Bleeding prophylaxis

The ideal treatment for HA should be preventive. Indeed, the implementation for prophylactic coagulation factor replacement therapy for more than twenty years has shown a positive effect on the reduction in the number of joint bleedings and on HA development, particularly when applied prior to the age of four. ^19,20 In addition, a decline in the proportion of total knee replacement surgeries was demonstrated in a 3-decade cohort retrospective study, likely reflecting the benefit of prophylaxis.²¹ But other studies show that minor and moderate hemophiliacs experience a higher Fig. 1 Main mechanisms involved in hemophilic arthropathy. ADAMTS: A disintegrin and metalloproteinase with thrombospondin motifs; IL: interleukin; MMP: metalloproteinase; RBC: red blood cells; ROS: reactive oxygen species; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor. 2 A. Théron et al. / Osteoarthritis and Cartilage xxx (xxxx) xxx–xxx risk of developing joint pathologies than the general population, which might be related to asymptomatic intra-articular bleedings.^22,23 Indeed, some studies have reported ankle joint damage in patients with moderate to minor hemophilia, in relation with microtraumas consecutive to physical activities.^24,25 Current prophylaxis therefore reduces the occurrence and duration of hemarthroses, but the impact of nano- and micro-bleedings on HA is still under debate.²⁶

Local treatments
To date, there are only palliative treatments for HA, primarily for pain relief using analgesics. In addition, local treatments such as infiltration of corticosteroids or hyaluronic acid can be prescribed to patients. In the event of predominant synovitis, surgical, chemical or radiation-induced synoviectomy is an option that can improve and slow-down the progression of joint amage.²⁷ Recent studies have reported promising results of ankle joint distraction with clinical and structural improvement in hemophilia patients.^28,29 This technique has proved its interest in other rheumatic diseases such as OA, with clinical and radiological improvement of the joints.30 External fixators are fairly well tolerated during the 10-weeks treatment period, although this is an invasive technique with an increased risk in hemophilia patients.²⁸ To date, there is no data on patients treated with inhibitors, who are at greater risk of bleeding during invasive procedures and more affected by arthropathy. ^31,32 Moreover, this technique cannot be applied to all the joints that may be affected in hemophilia patients.30 Finally, in case of dramatic damage to cartilage and/or bone, surgeries for arthrodesis or prosthetic replacement of the joint are indicated.³³

Targeted treatments
In hemophilia, dysregulated fibrinolysis has been associated to HA occurrence. Inhibiting the fibrinolytic system has been therefore evaluated as a therapeutic option. As a result, intra-articular injection of small interfering RNA directed towards protease-activated receptors 1-4 or anti-plasmin antibodies have been shown to attenuate synovitis and plasmin-induced cartilage damage in hemophilic mice.^34,35 A number of anti-inflammatory treatments have been tested in vitro and/or in vivo to inhibit synovial inflammation in HA models. Conventional anti-inflammatory drugs have failed to demonstrate a long-term effect in preventing HA.³⁶ However, the administration of IL4, IL10 or IL4-IL10 fusion protein has been reported to attenuate bloodinduced cartilage damage in hemophilic mice although no clear impact on synovial inflammation was observed.^13,37,38 By contrast, the use of anti-IL6R antibodies as an adjunct to FVIII therapy has been described to reduce synovial hyperplasia and macrophage infiltration and protect from HA.³⁹ Similarly, a treatment with anti-TNFα antibodies was shown to attenuate macrophage accumulation in the synovium of hemophilic mice and to reduce synovial thickness and vascularity in patients with HA.⁴⁰
Iron, the major trigger of synovial inflammation, is another potential target in HA. The use of iron chelators has therefore been
tested with the final aim of reducing cartilage degradation but in vivo studies have reported disappointing results.^2,41,42
Finally, other studies have targeted bone remodeling in order to slow down the harmful consequences of joint damage on the subchondral bone as described in HA. Bisphosphonates, the main therapy for bone remodeling in case of osteoporosis, have been
shown to improve the bone mineral density and to reduce bone resorption in patients with hemophilia.⁴³

Currently, none of the proposed treatments has entered into the clinics highlighting an urgent need for new therapeutics for the
management of HA in hemophilia patients. In this particular disease where unpredictable repeated intra-articular micro- and nanobleedings lead to irreversible joint lesions, the availability of treatments that could prevent or slow-down blood-induced alterations would be of high interest for the community. One potential innovative strategy would be to rely on cell therapeutics, in particular using MSCs that are under clinical evaluation for the treatment of more prevalent rheumatic diseases such as RA and OA.

MSCs-based treatments in rheumatic diseases

Generalities on MSCs

MSCs have been originally isolated from the bone marrow but have since been found in many other tissues such as adipose tissue,
umbilical cord, deciduous teeth pulp and synovial membrane. The International Society for Cell Therapy has defined MSCs according to three criteria, including the ability to adhere to plastic, the expression of a panel of markers ((cluster differentiation) CD73+, CD90+, CD105+, CD11b-, CD14-, CD34-, CD45- and Human leucocyte antigen DR isotype-) and the capacity to differentiate into the three mesenchymal lineages (chondrocytes, osteoblasts and adipocytes).⁴⁴ The therapeutic interest of MSCs has first been evaluated based on their differentiation capabilities with the aim of regenerating damaged tissues but since their paracrine activity has gained much attention. Indeed, MSCs release a large variety of soluble factors that influence neighboring cells in the microenvironment. In addition to their immunomodulatory capacity, MSCs have been demonstrated to inhibit fibrosis, apoptosis, oxidative stress and, stimulate angiogenesis, cell recruitment and proliferation. More recently, most of these factors have been shown to be packaged within extracellular vesicles (EVs) that are nanovesicles produced in a spontaneous or inducible
manner and largely involved in intercellular communication.⁴⁵ EVs possess similar properties as the parental MSCs and are now widely investigated as new therapeutic options in regenerative medicine.⁴⁶

MSCs-based therapy in inflammatory arthritis and OA

The immunosuppressive properties of MSCs make them an attractive option for the treatment of inflammatory rheumatic diseases such as RA.⁴⁷ In the murine model of collagen-induced arthritis, MSCs have been shown to reduce the clinical signs of arthritis and to induce a regulatory immune phenotype.48–50 The beneficial effect of MSCs was attributed to IL6-dependent production of prostaglandin E2 involved in the immune response polarization towards a Th2 profile and the generation of T regulatory cells induced by glucocorticoid-induced leucine zipper. ^50,51In a recent review of the literature on the clinical trials that have evaluated MSC-based therapy for RA, a good safety profile has been reported but insufficient proof of efficacy has been demonstrated likely related to the enrollment of patients with a long history of the disease and heterogeneity in the sources of MSCs and manufacturing protocols.⁵² Further evaluation using more standardized MSC therapy protocols in sub-groups of patients more amenable to benefit from therapy would foster clinical application of MSCs in RA.
MSCs are also of interest as therapeutics for OA, a degenerative rheumatic disease whose prevalence increases with age.⁵³ The ability of MSCs to differentiate into chondrocytes or osteoblasts made them attractive cells for the repair of altered cartilage or bone in OA patients.^54,555 Nevertheless, most of the studies focused on their paracrine activities. Adipose tissue-derived MSCs (ASCs) have been reported to protect chondrocytes from OA-associated degeneration and exert anti-apoptotic and anti-inflammatory effect on both chondrocytes and synoviocytes from OA patients.^56,57 In the collagenase-induced murine model of OA, MSCs protect cartilage A. Théron et al. / Osteoarthritis and Cartilage xxx (xxxx) xxx–xxx 3 and bone from alterations associated with OA.58–60 The therapeutic interest of MSCs has also been evaluated in several phase I/II clinical trials with encouraging results.^61,62 The meta-analysis of the 15 randomized controlled trials that have evaluated MSC-based therapy has concluded on the safety and efficacy of MSCs for OA treatment, with improvement of pain and functional scores in patients. If the improvement can be considered as modest (20 to 30%), structural efficacy of MSCs has still to be demonstrated and further evaluation in phase III trials is needed to firmly conclude on the interest of MSCs in a broader panel of patients. More recently, MSC-derived EVs have drawn attention as potential cell-free replacement therapy to MSCs due to their inferior immunogenicity and lack of tumorigenicity or differentiation potential, as well as easier management. Preclinical data are promising but evaluation of this innovative strategy in clinical trials is needed (for review, see ⁶³). The many symptoms and alterations on the joint compartments that have been described to be common in RA, OA and HA suggest that MSCs might be an effective therapy in reducing bleeding-related cartilage degradation and synovial activation. Indeed, MSCs might dampen the inflammatory response in the synovial membrane and cartilage, prevent chondrocyte apoptosis and reduce the catabolic activity of chondrocytes in favor of their anabolic activity. Furthermore, the antioxidant capacities of MSCs should also lower the oxidative stress related to the production of ROS induced by hemosiderin deposits in the synovial fluid.^64,65

MSCs in the management of HA Although MSCs have been initially investigated in regenerative medicine for their capacity to differentiate into different types of mature cells able to regenerate a functional tissue, the current main application of MSCs relies on their trophic properties. Through the production of various types of molecules that can be secreted as single molecules or within the cargo of EVs, they have proved their therapeutic interest in rheumatic diseases suggesting they might be used for HA treatment (Fig. 2).⁶⁶ MSCs as cell factory for coagulation factors To date, MSCs have mainly been studied as cell factories to deliver coagulation factors in hemophilia (Table I). Compared to in vivo gene therapy approaches, genetically engineered MSCs have the advantages of being poorly immunogenic and displaying immunosuppressive functions to bypass the host immune response to viral vectors. In addition, they express TF and phosphatidylserine, known to play a role in clot formation and coagulation.^67-71 Several studies have reported the production of therapeutic levels of porcine or human FVIII after transplantation of viral vector-transduced MSCs in hemophilia mice.^72-74 However, following transplantation of gene-modified MSCs in hemophilia A mice, FVIII activity rapidly returned to basal levels due to the generation of anti-FVIII neutralizing antibodies. Similar results were obtained using murine transgenic MSCs or human umbilical cordderived MSCs expressing the B-domain-deleted human FVIII (BDDhFVIII), which in its recombinant form, is the current standard of care for hemophilia A or, murine and human MSCs engineered to produce human FIX.^75-79In these two cases, production of BDD-hFVIII or FIX was observed up to four weeks and hFVIII inhibitors were detected in mouse plasmas. MSCs derived from hFVIII-overexpressing induced pluripotent stem cells allowed the production of therapeutic levels of hFVIII in hemophilia A mice for three weeks but the production declined to basal values at four weeks.⁸⁰ To overcome the production of neutralizing antibodies, different strategies have been tested. One of these is the implantation in utero of placenta-derived human MSCs transduced with BDD-hFVIII-expressing lentiviral vectors in wild-type fetuses from pregnant mice. Immunotolerance was claimed with BDDhFVIII expression for at least ten days.⁸¹ In another study, engraftment of BDD-hFVIII-overexpressing MSCs was detected up to twelve weeks when implanted at neonatal age in mice.⁸² Interestingly, neonatal implantation of native MSCs with BDD-hFVIII-overexpressing endothelial colony-forming cells increased the engraftment of the endothelial progenitors for at least twenty-six weeks and significantly attenuated bleedings in hemophilia mice. Another approach relied on optimizing the route of administration. Intra-articular or intramedullar administration of hFVIII-overexpressing autologous MSCs allowed sustained production of hFVIII for at least one or twelve months in FVIII-deficient mice or outbred adult dogs, espectively, while the production was not persistent after subcutaneous implantation.^83,84

Fig. 2

Potential mechanisms of action of mesenchymal stromal cells-based therapy to counteract hemophilic arthropathy.

Table I

Therapeutic use of MSCs in hemophilia.

In a more recent study, autologous MSCs overexpressing ovine FVIII engrafted easily in multiple organs after intraperitoneal injection and secreted elevated levels of FVIII for at least fifteen weeks. 85 This improvement was related to the absence or low levels of circulating inhibitors of hFVIII compared to subcutaneous implantation. Other tested strategies included the use of non-viral transduction methods such as nucleofection of engineered ASCs leading to high levels of human factor IX (hFIX) in plasmas of immunodeficient mice78 and the use of 3D porous hydroxyapatite-Poly (lactic-co-glycolic acid) scaffold for long-term engraftment of MSCs and sustained delivery of hFIX for twelve weeks in hemophilia B mice.⁸⁶ In another approach, the differentiation of human ASCs by an endothelial microenvironment was associated with an increased endogenous expression of functional hFVIII suggesting that non-genetically modified differentiated MSCs might restore FVIII activity in the vascular compartment.⁸⁷ Finally, an interesting study reported the therapeutic interest of adult-derived human liver stem cells (ADHLSCs), which display a hepatomesenchymal phenotype and express hFVIII, in one patient with hemophilia A.88 Five intravenous infusions of different doses of ADHLSCs for fifty days resulted in a temporary decrease in hFVIII requirement for the fifteen subsequent weeks and fewer bleeding complications during physical activities even though no significant increase in FVIII activity was detected in patient’s blood. In summary, MSCs genetically modified or activated by a sustainable microenvironment for the expression of coagulation factors have many advantages such as absence of cytotoxicity and long-term expression of the transgene provided that you aim at extending their half-life after implantation.

MSC-based therapy for hemophilic arthropathies

There is little data on MSC-based therapy relying on their endogenous paracrine activity to counteract arthropathy development in hemophilia. The first study that aimed to evaluate the impact of intraarticular injections of non-genetically engineered MSCs in HA has been performed in an experimental hemarthrosis rabbit model, which consists in two injections of fresh autologous blood twice a week for three consecutive weeks.⁸⁹ Autologous bone marrow-derived MSCs (BMMSCs) were injected ten days after the last injection of blood and the rabbits were sacrificed twenty-eight days later. Results were ambivalent with slightly higher cartilage thickness in the MSC-treated group compared to the hemarthrosis control group but the release of TNFα, IL1β and IL4 from synovial tissues was similar in both groups. Other results (surface cartilage structure, macroscopic evaluation) were descriptive and quantitative analyses were missing to firmly conclude on a benefit.
Nevertheless, other studies have reported interesting results. The intraperitoneal transplantation of haploidentical ovine MSCs transduced to express porcine FVIII in two sheeps with hemophilia A resulted in the resolution of existing hemarthroses and termination of spontaneous bleedings while damaged joints fully recovered.⁹⁰ No porcine FVIII was detected in the blood of animals that was explained by the robust immune response to FVIII. Interestingly, large numbers of MSCs expressing FVIII were observed post-mortem in the synovium of the joints that exhibited hemarthrosis at the time of implantation suggesting that MSCs can home to the site of injury where they persisted for more than three months. Engraftment of luciferase-expressing MSCs was also
reported in the cartilage of mice 28 days after intra-articular injection66. In that study, hemostatic effect of hFVIII-expressing MSCs, but not of non-transduced MSCs, was observed in FVIII-deficient mice together with the reduction of hemorrhage-induced synovitis, including synovial

Conclusions and perspectives

Currently, there is some evidence that the paracrine activity of MSCs may dampen blood-induced alterations in cartilage but it warrants to be demonstrated on other joint compartments, in particular on the synovial membrane that plays a key role in inflammation, angiogenesis and oxidative stress activation in HA. The promising data obtained in vitro on chondrocytes and the demonstration of safety in gene therapy-based strategies highlight MSCs as promising therapeutics for treating patients with HA. The available data from patients are case reports and therefore represent studies for safety evaluation with low-level evidenced proofs of efficacy. However, hemophilia is a rare disease that represents a niche indication for MSC-based therapies. It will therefore be difficult to design clinical trials for treating/delaying arthropathy in this indication. A number of issues will need to be addressed in animal models before clinical evaluation in humans. One of these will be to identify the right dose, the best route and the right therapeutic window for MSC administration since multiple joints can be impacted by bleedings and this will determine whether a local or systemic route should be envisioned. Systemic injections might be prioritized as MSCs have been shown to target the diseased joints.88 The window for MSC administration is of importance and will be particularly difficult to determine since a number of hemarthroses are asymptomatic and irreversible lesions may occur as soon as 48 h of bleedings. While the therapeutic efficacy of MSCs has still to be demonstrated in HA, we may already discussed on the possibilities to evaluate MSCderived EVs as novel medicinal biological drugs for HA treatments. Most of the paracrine effects of MSCs have been reproduced by their EVs and MSC-derived EVs are effective to prevent OA and RA development in murine models.^92,93 Clinical translation of MSC-derived EVs presents several advantages compared to MSCs, including low risk of blood toxicity on EVs, no risk of tumor formation or differentiation and, off-the-shelf availability of EV batches as soon as a hemarthrosis occurs. Such approach warrants to be tested in the near future.

Role of the funding source

We acknowledge the Agence Nationale pour la Recherche for support of the national infrastructure: “ECELLFRANCE: Development
of a national adult mesenchymal stem cell based therapy platform” (PIA/ANR-11-INSB-005).

Authors’ contributions
All authors contributed to the analysis and interpretation of the data, drafting of the article, critical revision of the article for important intellectual content and final approval of the article.

Acknowledgments
We acknowledge funding support from the Inserm Institute, the University of Montpellier and the Coordination Médicale pour l’Etude et le Traitement des maladies Hémorragiques et constitutionnelles (CoMETH). We are grateful to the Association Française des Hémophiles for its support and funding.

Competing interests

The authors declare no competing interests.

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