Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review

Abstract

Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.

Keywords: drug delivery system; exosomes; immunomodulation; mesenchymal stem cells; nano-medicine; therapeutics.

Figure 1

(A) Biogenesis, secretion, and cellular uptake of exosomes. The biogenesis of exosomes starts from the (i) early endosomes which mature into (ii) late endosome, then (iii) multivesicular bodies are formed by the invagination of late endosomal membrane, which is finally secreted as (iv) exosomes to the extracellular matrix in a mesenchymal stem cell. (B) The secreted exosomes are uptaken by a recipient cell in several ways viz. (a) clathrin-mediated uptake, (b) receptor-mediated uptake or by the (c) membrane fusion event.

Figure 2

Isolation of Exosomes: exosomes are commonly isolated from the conditioned media. Some common preprocessing steps are required for both the techniques, including collecting conditioned media from MSCs, performing a centrifugation round at 2000× g for 30 min to remove debris. Furthermore, the conditioned media can be subject to any of the two techniques including, Ultracentrifugation (1) or Kit-based methods (2) for isolation of exosomes. These exosomes can be further used for characterization, aliquoting, and storage for future experiments.

Figure 3

Mesenchymal stem cell exosome cargo in modulating cardiovascular diseases, neurological disorders, kidney diseases, liver diseases, cancer, and lung diseases.

Figure 4

The multifaceted nature of exosomes: Exosomes can carry varied cargo including DNA, RNA, miRNAs, enzymes, proteins, ESCRT components, etc. They can also serve as drug delivery systems through their ability to carry and transfer a wide range of molecules, such as hydrophobic and hydrophilic drugs. Multiple molecules, including dyes, imaging agents, etc. can also be linked to exosomes for their visualization and characterization.

Figure 5

The challenges of bringing exosomes from bench to bedside: Even after the multifactorial facets of MSC derived exosomes, there are still many challenges in their ultimate translation into a product; these may include low yield, uncertainty in yield, potency, half-life, biodistribution, source selection, risk of off target functioning, etc.