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Cell-free therapy is a therapy in which secreted molecules from cells are used as the therapeutic material for treating various medical conditions.

Types and limitations of existing cellular therapies

Cell therapy or cellular therapy refers to the introduction of autologous or allogenic viable cells into a patient in order to treat a medical condition[1].

There are two major types of cell based therapies, namely: (1) Stem cell and (2) Non-stem cell based therapies. In the former case, adult stem cells such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the most widely used in clinical settings to treat a variety of conditions such as disorders of the blood and immune system, cancer and degenerative diseases to name a few[2]. Currently, the only stem cell based therapy approved by the U.S Food and Drug Administration (FDA) is hematopoietic (or blood) stem cell and progenitor cell (derived from cord blood) transplantation for treating certain cancers and blood disorders[3][4]. Clinical trials for the treatment of other conditions employing MSCs are underway[5][6]. Despite being a promising candidate to treat a variety of medical conditions, stem cell based therapies are also associated with certain limitations which are classified into 4 categories.

(1) Intrinsic factor- Rejection of the transplanted cells based on the origin of cells (autologous or allogenic).

(2) Cell characteristics- (a) Tumorigenic potential, due to the ability of the stem cells to self-renew and (b) Ability of the stem cells to change into inappropriate cell type.

(3) Extrinsic factors-  (a) Infections, arising due to lack of donor history, (b) Potential for the contamination of the product arising due to the cell handling procedures, raw materials (growth media components, chemicals etc.) and (c) Low cell viability during administration.

(4) Clinical characteristics- (a) Undesired immune response (for example, Graft versus Host Disease (GVHD), arising due to allogenic stem cell transplantation), (b) Injection site reaction, (c) Administration route, if inappropriate can result in engraftment at an unwanted location, (d) Lack of therapeutic efficacy arising due to several factors (for example: use of immune suppressives), (e) Lack of knowledge regarding optimal dosage and timing of injections, (f) Less observable clinical benefits due to low engraftment of cells[7][8][9][10].

Non-stem cell based therapies are generally somatic cells (T cells or genetically modified T cells, fibroblasts, and keratinocytes to name a few) that are isolated from human, expanded invitro and administered back to the patients in order to effectuate the medical condition[11][12][13][14]. Currently, there are only 9 non-stem cell based products available which are approved by FDA, of which 60% of the products employ Chimeric Antigen Receptor T cells (CAR-T cells) to treat B cell lymphoma[15][16] and the rest 40% are scaffold based cellular products[17]. Although CAR T-cell immunotherapy has produced remarkable clinical responses, yet there are several challenges that limit the therapeutic efficacy of CAR T-cells especially in solid tumors and hematological malignancies[18]. These include:

(a) Antigen escape[19].

(b) Limited CAR T-cell tumor infiltration[20].

(c) Immunosuppressive microenvironment[21]

(d) CAR T-cell associated toxicities[22]

Scaffold based cellular products are by far considered to be safe and an effective alternative to current cell based treatments (which mainly focuses to deliver the cells either systemically or intradermally) in favoring enhanced cell viability, retention and functionality at the wound site[23].

Cell-free therapy: Advantages over cell based therapies

In the past decade there has been an increasing evidence that it is the bioactive factors secreted from the transplanted cells that matter during the treatment than the cell transplantation alone[24] [25]. Cell-free therapies have been quite extensively studied for its potential application in cancer[26], regenerative medicine[25]and inflammatory diseases to name a few[2]. This kind of therapy is now considered as the next generation therapeutic technology. Cell-free therapies overcome the limitations and risks posed by the cell based therapies in that[27][28][29][30]

(a) It lowers the risk associated with pulmonary embolism after intravenous (IV) administration.

(b) It avoids the risk of tumorigenic potential as cell-free products cannot self-replicate.

(c) It is non-immunogenic due to the limited number of antigenic components.

(d) It avoids exogenous infections which is more prominent in cell based therapies.

(e) It can be stored for a relatively long periods of time without any toxic cryopreservant such as DMSO.

(f) It is able to infiltrate the target organ more effectively (Targeted drug delivery).

(g) Therapeutic efficacy can be equivalent to or more effective than cell based therapy.

Cell-free Approaches

Broadly, there are two major types of cell-free strategies: (a) Acellular material based scaffolds[31] and (b) Endogenous cell targeting through delivery of bioactive factors[32]. These two fields are the subjects of extensive research nowadays.

Acellular material based scaffold

The field of using acellular material based scaffolds has significantly increased over the past few decades owing to its potential application ranging from promoting tissue formation through mechanical support (Traditional approach) to organize and vascularize tissues (scaffold containing bioactive molecules) (Current approach) and to modulate endogenous cellular processes such as inflammation, direct differentiation and recruit cells for repair (Emerging approach). Additionally they also provide structural support to the exogenously applied cells to attach, grow and differentiate in-vivo[31].

Acellular biomaterials are aimed to enhance the repair process of native cell populations after injury or with disease, for example, repairing cartilage tissue, treating patients after myocardial infarction and bone tissue engineering[33][34][35][1] Although cell-seeded scaffolds have given promising results in Tissue Engineering and Regenerative Medicine (TERM), yet there are quite a few challenges in order to maximize the clinical benefits[36]. Some of the major challenges include:

(a) Cell type, seeding and distribution on a scaffold

(b) Design of the scaffold (composition, i.e., natural, or synthetic polymers, topography and architecture) which influences cell attachment and its behavior (41).

In contrast, acellular based scaffolds have extremely low immunogenicity due to the absence of employment of any allogenic cells on a scaffold, i.e., these types of acellular scaffolds are loaded with all the necessary cues and signals in order to drive the repair process efficiently[37] . The current limitations of acellular scaffolds in TERM include design parameters of scaffolds for therapeutic efficacy, biocompatibility, its degradation rate and bioactivity[38].

Endogenous cell targeting

Targeting several endogenous cell moieties have also been explored to treat a variety of disease conditions such as cancer and degenerative disorders without the necessity of cell therapy [39]. There are different ways by which an endogenous cell moiety can be targeted based on the disease condition. These include:

(a) Small molecules

(b) RNA therapeutic strategies

(c) Direct reprogramming

(d) Growth factors and proteins.

Small molecules

Over the past few decades, there has been a tremendous focus in utilizing the small molecule (targeting a specific cell moiety) to treat cancer and also to enhance the repair process after injury or with disease [40]. By far, about 89 small molecule anti-cancer drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China [41]. Sorafenib and Axitinib are the two most commonly used drugs to treat cancer . Sorafenib exerts its inhibitory action on a specific class of proteins called kinases which are involved in favoring tumor cell proliferation and angiogenesis [42], whereas, Axitinib works by blocking the vascular endothelial growth factor receptor  (VEGF-R) tyrosine kinase 1,2 and 3 resulting in reduced angiogenesis [43]. Thus these two drugs ultimately aim to either kill or stop the growth of cancer cells. Similarly, these small molecules have also shown encouraging results in regenerative medicine as well, for example, prostaglandin E2 is known to have a regenerative role in ischemic myocardium post myocardial infarction (MI). It activates and mobilizes the endogenous cardiac stem cell (Sca-1+cells) population to the infarct border zone and regulates their differentiation into cardiomyocytes [44]. Single or combination of small molecules can also be utilized to solve a disease condition [45]. The employment of small molecules has certain advantages as therapeutics in some aspects which are:

(a) Because of their small size, these can be effectively used to target extracellular proteins or intracellular receptors due to their ability to pass through the cell membranes easily [46].

(b) Can be easily manufactured by chemical synthesis and therefore these are often inexpensive [47].

(c) Easy to store and transport.

(d) Patient compliance majorly due to higher oral bioavailability.

(e) Extremely stable.

(f) Variety of formulations available.

(g) Driver of innovation in research and development [48].

However, small molecule drugs still face some challenges majorly of which are drug resistance and low response rate [41].

RNA therapeutic strategies

RNA therapies generally work by manipulating gene expression or produce therapeutic proteins [2]. There are a variety of RNA therapeutic strategies that can be utilized for pathologies with distinct genetic targets including infectious diseases, cancer or immune diseases [49]. It also finds its use in regenerative medicine as well [50].

Modified messenger RNA (ModRNA)

ModRNA is a type of synthetic messenger RNA (mRNA) containing non-standard residues. This is an improved version of the current mRNA therapy which faces certain challenges that limits the success rate of this therapy in clinical settings [51]. These include:

(a) Short half-life of mRNA, due to the presence of ubiquitous enzymes (ribonucleases (RNAses) )that degrades the unprotected mRNA [3].

(b) Inflammatory nature of exogenous RNA i.e., invitro transcribed foreign RNA can be recognized by certain innate immune system receptors which ultimately decreases the target protein synthesis in the cell. This recognition leads to the release of various inflammatory cytokines which when exceeds the limit results in programmed cell death (PCD) [52].

Contrary, the inclusion of the modified nucleosides such as uridine, pseudouridine or 5-methylcytosine in this mRNA can prevent the inflammatory reaction by escaping the recognition from the innate immune system while still translating this ModRNA into the target protein effectively in the cell [53]. This type of RNA are a potential candidate for developing cancer vaccines. These vaccines work by targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) and can specifically attack/destroy malignant cells that overexpress these antigens [54] [55]. ModRNA also finds its application in regenerative medicine, for example, repairing the damaged heart muscle tissue post myocardial infarction [56].

MicroRNA targeting

MicroRNAs or miRs are a kind of small endogenous, non-coding RNAs of about 18-22 nucleotides in length, that regulates coding gene expression and ultimately mediating changes in protein synthesis. miRNAs target mRNAs by binding to it (complementary binding) in order to exert their function. A single miRNA can have multiple mRNA targets and thus have the ability to influence many related genes which results in multifaceted effects on cell phenotype [57]. miRNA targeting therapy is currently explored in cancer diagnoses, improving outcomes of cancer treatment and also in regenerative medicine. There are two major strategies by which miR activity can be modulated based on the disease condition : (1) Overexpression, and (2) Down-regulation of miRNAs. For example, the tumorigenesis process is usually associated with either down-regulation of tumor-suppressive (TS) miRNAs or upregulation of oncomiRs or both [57]. In order to rectify the abnormal expression, two approaches can be as follows: (1) Importing exogenous miRNAs (TS miRNAs) or (2) Inhibit the oncogenic miRNAs by applying anti-miRNA oligonucleotides (AMOs) [58], miRNA antagomirs, antisense oligonucleotides (ASOs) to name a few [59]. Also, mounting evidence have shown that modulating miRNAs provided promising results in bone-regeneration [60], wound-healing [61], skeletal muscle and cardiac regeneration [62], angiogenesis [63] and neurogenesis, majorly by promoting endogenous cell proliferation after injury [64].

Despite the great success of miRNA therapeutics in pre-clinical studies, very few clinical trials are being conducted currently. This is due to certain limitations associated with this kind of therapy which include:

(a) Efficient delivery of miRNA to the target site: (a) Chemical modifications of miRNA mimetics ( to avoid its degradation from nucleases) prevents its recognition and loading onto Argonaute and RNA-induced silencing complex (RISC). This will lead to lesser therapeutic effect as loading of miRNA into Argonaute and RISC is important to exert its function [65] [66]. (b) Liposome nanoparticles, one of the delivery strategies of miRNA, are relatively large enough which makes it difficult to gain entry into the extracellular spaces, especially of solid tumors to exert its effect [67].

(2) Another challenge associated with miRNA therapeutics is the activation of innate immune system which leads to target cell death upon recognition of exogenous miRNA molecules [68].

(3) Off target effects, due to the ability of a single miRNA to target many several mRNAs (otherwise known as “too many targets for miRNA effect”), this non-specific interaction could be either beneficial or trigger unknown consequences which can lessen its therapeutic effect [68]. Another off-target effect could be seen when the therapeutic miRNA is not tissue/cell-type specific. For example, obtaining a therapeutic benefit by modulating target gene expression in target cell type (say, cancer cells) can be accompanied by modulating this same gene expression in non-target cell-type (say, normal cells) if miRNA selection is not tissue/cell-type specific. Such an interaction can lead to toxicity [69].

Direct reprogramming

Direct epigenetic reprogramming is a very useful technique and a novel approach that converts an adult differentiated cell into an another differentiated cell, while bypassing the pluripotent stem cell fate (and the potential risk of tumor formation) [70]. This technique is mostly explored in the field of regenerative medicine, for example, generating functional cardiomyocytes from  endogenous fibroblasts post myocardial infarction [71]. Recent research has indicated that there are 5 different approaches which can directly reprogram an adult differentiated cell into another phenotypic cell. These include: (a) transcription factors(81), (b) epigenetic regulators(82), (c) miRNAs, (d) small molecules and cell penetrating peptides and (e) pluripotency factors for indirect reprogramming.(83)

Transfecting the host cell that allows for the expression of exogenous DNA or RNA drives the phenotypic changes via the activation of certain genes involved in reprogramming(84). Cell transfection can be either transient or stable, with the former being advantageous in that it allows for the expression of the exogenous DNA or RNA without the need to be integrated into the host cell genome. This can be achieved using non-viral techniques such as liposome and non-liposome mediated transfection, dendrimer-based transfection and electroporation, and non-integrating viral systems such as adenovirus and adeno-associated virus (AAV) can also be used to transiently express the exogenous DNA or RNA. Unlike transient transfection, stable transfection allows the exogenous DNA or RNA to be integrated into the host cell genome permanently(85). To achieve this, techniques such as microinjection and integrating viral systems (Lentiviral and γ-retroviral vectors) can be utilized. Small molecules and cell penetrating peptides have also been shown to regulate the process of transdifferentiation either alone or with a combination of exogenous DNA or RNA with the aim of increasing the efficiency of transdifferentiation(86,87).

Cellular reprogramming technology holds the potential to also generate various immune cell types for cancer immunotherapy(88). For example, in the context of cancer, M1-macrophages are involved in tumor cell clearance by producing pro-inflammatory cytokines but signals produced from tumor cells can polarize the macrophages into M2 anti-inflammatory type which induces an immunosuppressive environment and in turn supporting tumor development making the condition worse(89). To combat this, invitro studies have shown that macrophages can be generated by direct cellular reprogramming on fibroblasts via the combined expression of certain factors/genes (PU.1 and CEBPα/β), which after a week attained macrophage like phenotype with the ability to mount inflammatory response which is crucial for tumor clearance. Similarly, reprogramming into dendritic cells, granulocytes, NK cells, T cells and B cells were also shown.(88,90)

An interesting aspect of direct reprogramming in cancer therapy is, to modulate the cell fate of cancer cells which leads to its loss of tumorigenicity. For example, inducing benignity and antigen presentation in cancer cells via cellular reprogramming (91). This field of direct cellular reprogramming is still evolving and hence a large number of studies (invitro and pre-clinical) have to be conducted in order to enter the clinical trials.

Growth factors and proteins

Growth factors (VEGF, SDF-1, IGF-1, FGF-1, HGF, PDGF, BMP family (BMP-2 and BMP-7) to name a few) are proteins that are known to influence cell growth, proliferation, motility, survival, adhesion, differentiation and also regulate angiogenesis via the activation of specific cellular signal transduction pathways(92). Growth factors exert their action by interacting to its receptor either in a diffusible manner (e.g., by endocrine, paracrine, autocrine and intracrine pathways) or in a non-diffusible manner (e.g., by juxtacrine and matricrine pathways) or both (93).

These growth factors are majorly utilized for regenerative medicine applications. For instance, BMP-2 and BMP-7 (FDA approved) are involved in bone regeneration (94). Similarly, growth factors such as PDGF-BB, IGF-1, FGF-7 (KGF) (all FDA approved) are used to treat ankle fusion, hindfoot, primary IGF-1 deficiency, spinal fusion and gastrointestinal injury (95). Like other therapeutic agents, growth factor based therapies are also associated with certain limitations which hinders its translation into clinical applications. These include:

(a) Protein Stability and half-life

(b) Low yield of recombinant protein

(c) High costs and possibilities of side effects, due to multiple administrations in order to attain optimal concentration at target site.

(d) Sub-optimal efficacy.(95)

(e) Off-target effects, i.e., if organ-specific growth factors for achieving therapeutic benefit are not selected, then the modulation expected by the desired growth factor can also involve other organ apart from the target organ which can hence result in undesirable effect.(96)

(f) Lack of appropriate delivery systems.(97)

It was due to these limitations that led to an advanced research which focuses on various approaches to enhance the therapeutic efficacy of exogenous growth factors. Briefly these approaches include:

(a) Introduction of stabilizing mutations in order to increase the half-life of the protein.(98)

(b) Identification of protein variants (e.g., by yeast and phage based library display platforms) with improved stability and expression yield.(99)

(c) PEGylation to enhance the half-life of proteins which can lead to reduced dosing frequency.(100)

(d) Use of library screening methods to isolate variants which have an (a) increased receptor binding affinity and (b) decreased receptor internalization.(101)

(e) Engineering growth factors in such a way that allows them to also engage in alternative signaling pathways for the purpose of enhanced therapeutic effect.

(f) Strategies involving protein engineering within the microenvironment in order to achieve maximum therapeutic efficacy for regenerative medicine applications.(102)

(g) Use of appropriate delivery systems which are safe and cost-effective such as growth factor delivery through (a) decellularized ECM, (b) exogenous engineered biomatrices to name a few.(103)

Mesenchymal stem cells (MSCs) as a source of therapeutic molecules for cell-free therapy

MSCs are the most commonly used cells for cell-based therapy as they do not form teratomas, confer low immunogenicity as they express relatively low levels of major histocompatibility complex class I molecules and lack expression of major histocompatibility complex class II and co-stimulatory molecules (e.g., CD40, CD80, and CD86), they are not prone to triggering recipient immune responses  and are free of strict ethical concerns making it useful for both allogenic and autologous therapeutics. MSCs are known for its   marked potential in regenerative medicine due to its strong immunosuppressive and regenerative abilities and the  major therapeutic properties like anti-inflammatory, anti-fibrotic, anti-oxidant, and angiogenic effects of MSCs are due to their secretion of biologically active soluble products, including chemokines, cytokines, trophic factors, ECM proteins ,EVs, and exosomes, which can used as “next generation” therapeutic and diagnostic. Using cell-free products based on biologically active factors secreted by stem and progenitor cells allows to significantly reduce the risks associated with a direct cell injection, while maintaining efficacy under wide manufacturing scalability and modification potential like fractionation, concentration, and combination with various carriers. Therefore, application of “cell-free therapeutics” based on the components secreted by MSC represents a rapidly developing and promising approach in regenerative medicine

Extracellular vesicles are cell-derived membrane particles ranging from 30 to 5,000 nm in size, including exosomes, microvesicles, and apoptotic bodies. They are released under physiological conditions, but also upon cellular activation, senescence, and apoptosis. They play an important role in intercellular communication. Their release may also maintain cellular integrity by ridding the cell of damaging substances.

Exosomes are the smallest vesicles (30–100 nm) released by the fusion of multivesicular bodies containing intraluminal vesicles with the plasma membrane. Because exosomes are formed by budding from early endosomes, they have a lipid bilayer membrane, which protects the resident genetic material (DNA, mRNA, miRNA, pre-miRNA, and other non-coding RNAs), lipids, and proteins during transportation to target cells. The most common exosomal surface proteins are members of the tetraspanin family, a group of scaffold membrane proteins including CD63, CD81, and CD9, which serve as markers. Depending on their characteristics, exosomes can be used for disease diagnosis, drug delivery, and as therapeutic agents. Exosomes engage in specific interactions with the recipient cells, promoting information and material exchange between widely separated anatomic sites.

Like stem cells, exosomes exhibit many biological activities and have shown therapeutic potential in several organ system and disease contexts. For example, exosomes may: protect against cisplatin-induced renal oxidative stress and renal cell apoptosis, enhance myocardial viability and prevent adverse remodeling after ischemic injury, promote angiogenesis in the setting of myocardial infarction, protect the intestines from enterocolitis, improve hypoxia-induced pulmonary hypertension, and promote functional recovery after stroke. At least in part, such therapeutic effects of exosomes are attributable to their ability to induce angiogenesis as well as regeneration and proliferation of epithelia. Also exosomes exhibit immunomodulatory (largely anti-inflammatory) effects, which are specifically known for down-regulation of interferon-γ secretion and T-cell polarity alteration— are able to stabilize skin graft survival. The efficacy of exosomes is similar to cell-based therapy with lesser limitations, indicating that exosomes have potential as next-generation (i.e., cell-free) therapy.

Although exosomes showed promising results, yet there are certain concerns linked to MSC-Exosomes which include (a) Lack of standardization of molecular characteristics, comparability, and reproducibility, (b) Difficulty in obtaining high-purity exosomes of defined size, (c) Biodistribution, toxicity, and clearance of MSC-Exos after injection; and (d) The pathways and recognition signals of MSC-Exos for target cells and organs need to be identified. 

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