Stem Cell Delivery Routes: From Preclinical Models to Clinical Applications

Basic experimental research on stem cells has paved the way towards an array of possible clinical applications. Mesenchymal stromal/stem cells (MSCs), due to their multipotent properties and easily accessible sources, are the most studied stem cell types in a spectrum of diseases and injuries. Cell viability and dosage, delivery routes, homing and engraftment are some of the crucial factors that ensure the therapeutic efficacy of transplanted stem cell therapy in preclinical as well as clinical studies. In this chapter, we will introduce the types of stem cells and their derivatives that can be used for tissue repair and regeneration. In particular, the reasons behind the choice of certain cell types for transplantation and associated strategies are discussed based on knowledge gained on MSC research and its application for the treatment of human diseases. The administration route and cell carrier materials are among the factors that can influence the residence time, viability, and homing of stem cells.

The liver is at the crossroad of several vital processes, including metabolism, detoxification and immune surveillance. Chronic insults caused by a multitude of factors reduce liver functionality and, if left unchecked, can lead to lethality. Definitive cure of the damaged liver occurs through orthotopic organ transplantation, but the shortage of suitable organs, high costs and its invasiveness limit such an approach. Thus, new strategies to attenuate liver disease progression and restore function are being searched for. Cell therapy is resolute in some cases, and act as bridging therapy in others. Several cell types have been investigated both preclinically and clinically for their therapeutic efficiency. Stem cells are optimal candidates for reversing liver damage, due to their plasticity and capacity to secrete reparative factors. Among stem cells, MSCs are the most studied for their manipulability in vitro, and efficacy in vivo. MSCs play a therapeutic role in liver disease by homing to and engrafting in the injured liver, and by its ability to adopt a hepatogenic fate in some cases. In other instances, the secretome of injected MSCs favour liver regeneration and injury repair. When delivered through different routes including intravenous, intraportal, intrahepatic, intraperitoneal and through the hepatic artery, MSCs may confer different therapeutic efficacy. Cell survival in vivo, cell dosage, the extent of liver damage and microenvironment are other factors that determine the success of MSC-based therapy. In this chapter, the delivery routes used to target MSCs to the liver will be addressed.

The ocular surface is constantly exposed to the environment and is prone to severe injury or disease which may be responsible for vision loss. Serious corneal injuries may result in permanent vision loss and their treatment remains a clinical challenge. MSCs and their secreted factors (secretome) have extensively been studied for their regenerative properties in preclinical models. The plethora of cytokines and growth factors, as well as EVs released by MSCs, act in concert against scarring, neovascularisation and inflammation, and assist in the re-epithelialisation process of the ocular surface after injuries. Different routes of MSC and EV administration have been studied in preclinical models, and thereafter employed in the clinical setting in order to maximise the efficacy of MSC-based treatment for corneal disturbances. This chapter describes the possible routes of administration, including systemic, local and topical delivery of stem cells and their bio-products, and the associated efficiency of repair.

Stem cell-based therapies are promising for the treatment of various kidney diseases. MSCs have conferred protective and regenerative effects on renal cells. However, the major hurdle encountered is the delivery of a sufficient number of MSCs to the kidney to achieve therapeutic benefits. Several injection routes have been utilised to deliver cells to the kidney parenchyma. Only a small proportion of MSCs journey to the kidney when the systemic route is employed. Direct delivery routes, like renal artery injection, are promising but require surgery. Other cell delivery methods include kidney capsule injection, intraperitoneal delivery and intraparenchymal administration. Recently, a minimally invasive renal artery injection was also implemented to promote the delivery of a significant number of transplanted cells to the kidney. Several clinical trials have been performed using MSCs from different sources for the treatment of kidney diseases. The limited results available from clinical studies show that MSCs administration for the management of kidney diseases is safe and feasible.

Stem cell transplantation is promising for the treatment of injuries and diseases. Some concerns raised about certain aspects of cell therapy and associated risks have solicited utilising the “secretome” or proteinaceous secretions of the stem cells as an alternative therapy. The secretome of stem cells has been shown to be loaded with therapeutic biomolecules, such as growth factors, cytokines and EVs. Due to technological advances, knowledge and extensive molecular data on the secretome of stem cells, especially MSCs, are getting constantly updated. Soluble proteins or EVs are the main paracrine effectors of MSCs in tissue repair and regenerative activity at sites of injury. Extracellular vesicles, in particular, are currently under intensive investigation and can develop into a practical option for patient treatment in clinics. This chapter will deal with the promises of MSC secretome, taking as examples the data available from studies on the liver, cornea and kidney.

Improvement in MSCs culture and expansion, delivery, homing and engraftment are needed in order to achieve optimal therapeutic outcomes in the clinic. Strategies to enhance safe and efficient stem cells as well as associated bioproducts delivery to target organs in vivo are currently being implemented. Stem cell delivery medium including natural and synthetic biomaterials, cell encapsulation devices, biologic and artificial scaffolds have received much attention lately. An ideal cell delivery vehicle must fulfill certain criteria, such as maintaining the vitality and function of embedded cells, being biologically compatible and biodegradable, and allowing controlled release of biomolecules from the cells towards the target tissue. In this chapter, the strategies adopted to deliver MSCs to or enhance their therapeutic activity at sites of injury in the liver, ocular surface and kidney are described. New and remodelled delivery systems are required to ensure the successful translation of cell therapies to the clinics.

Stem cell-based therapeutic possibilities have revolutionised medicine. In order to maximise clinical outcome, it is essential to use the optimal cell type and dosage, and cell infusion routes, as well as determine the post-transplantation homing and engraftment efficiency of infused cells. Tracking the fate of transplanted cells is pivotal to monitoring their viability and distribution to the target organ. Several labelling techniques are employed to trace transplanted cells in vivo. In rodents, magnetic-, fluorescence- or luminescence-based imaging methods have been developed and tested for their capacity to evaluate the engraftment of transplanted cells. The majority of these modes of in vivo cell tracking are still in the preclinical phase of investigation. Acquisition of reliable images depends on the specificity of the signal of the labels used at a certain tissue depth. While longitudinal analysis is feasible in preclinical models, and usually relies on histological or molecular analyses for its confirmation, this is still undoable in the clinical setting. Further research in molecular imaging approaches and in ways to follow the in vivo fate of injected cells in humans are required.

The promises linked to stem cell-based therapy have encountered several hurdles on their way to clinical trials. Albeit the results obtained in preclinical studies have been encouraging, especially regarding therapeutic outcomes in several models of human diseases, this has not been the case in clinical trials using stem cells. MSCs have been mostly used in clinical studies, which limits us mainly to this cell type for the time being for clinical applications. A point that should be urgently evaluated before proceeding with cell therapy is whether this approach is applicable to all sorts of diseases, especially in cases where the microenvironment is no longer cell receptive. From a technical point of view, improvement is required at several steps of cell therapy: standardisation of MSC source and production, choice of cell injection route, cell dosage, frequency and timing of cell administration, cell tracking, cell homing and engraftment. Data regarding long-term MSC survival in vivo are scarce. In this chapter, the bottlenecks that refrain from the widespread use of MSCs in clinical applications will also be considered. Currently available and innovative solutions to tackle all these issues are discussed.

MSCs are promising for cell therapy of a variety of pathological conditions. MSCs can interact with the surrounding cells and environment and can be harnessed to confer therapeutic effects in several ways, as witnessed by progress in preclinical studies performed to date. However, translation into routine clinical practice is still trailing behind, as the beneficial effects seen in preclinical models could not be fully reproduced in clinical trial settings. The heterogeneity in bioprocesses that surround MSCs from their isolation to their transplantation is mostly responsible for the uncertain clinical outcomes. Yet, MSCs continue to be studied in a broad spectrum of clinical trials due to the MSC attributes that suggest that these cells will tip the balance towards finding an effective therapy for diseases hitherto incurable by other strategies. MSCs production should be standardised in order to optimize their output in the clinical settings. Very few of the registered clinical trials, performed with MSCs from diverse sources to date have published data. This is an area where not all negative results are negative, and publication of results should be encouraged. Negative results can help in devising better strategies in order to overcome difficulties and take us a step forward towards real therapy.

The preclinical successes of MSC-based therapy are not equalled in the clinical setting. Moreover, the translational advances of cell-based therapy are hindered by a plethora of factors that result in the heterogeneity of the clinical outcomes. Decades of research and development of MSC-based therapy have shown that transferring MSCs from bench to bedside is possible, but few clinical studies have reported favourable results. Rigorous control over MSC manufacturing steps, clarifying the mechanisms of action in each organ and disease, and the control of cell quality, as well as in-patient fate, are areas where much improvement is needed. Due to these critical points, stem cell medical tourism is not recommended. Especially, lack of patient protection, the use of MSC preparations with insufficient evidence of safety and efficacy are among factors that may lead to deterioration of health conditions. MSCbased interventions backed by preclinical studies and clinical trials showing feasibility and safety are clearly important before routine treatment with stem cells can be envisaged. Helped by artificial intelligence, data generated by high throughput technologies can be gathered and interpreted in order to increase patient-tailored lifesaving therapeutic efficacy of MSCs and MSC-based product such as extracellular vesicles.