The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles

Abstract

The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects rather than long-term engraftment and survival of transplanted cells. Given their ability to cross biological barriers and mediate intercellular information transfer of bioactive molecules, extracellular vesicles are being explored as potential cell-free therapeutic agents. In this review, we first discuss the state of the art of regenerative medicine and its current limitations and challenges, with particular attention on pluripotent stem cell-derived products to repair organs like the eye, heart, skeletal muscle and skin. We then focus on emerging beneficial roles of extracellular vesicles to alleviate these pathological conditions and address hurdles and operational issues of this acellular strategy. Finally, we discuss future directions and examine how careful integration of different approaches presented in this review could help to potentiate therapeutic results in preclinical models and their good manufacturing practice (GMP) implementation for future clinical trials.

Keywords: acellular therapy; cell therapy; exosome; extracellular vesicles; pluripotent stem cells.

Figure 1

Biogenesis and general composition of EVs. (A) Scheme describing the biogenesis of EVs: Microvesicles are produced via the outward budding of the plasma membrane whereas exosomes arise from the fusion of multivesicular bodies with the plasma membrane. Early sorting endosomes receive materials from endoplasmic reticulum, golgi and the endocytic pathway. Multivesicular bodies are generated through the formation of intraluminal vesicles in the late sorting endosome. (B) Illustration of nucleic acids, proteins and lipids that can be present in EVs (this list is not exhaustive). Exact nature of EV cargo depends on the cell type, culture conditions (i.e., stress) and pathological state.

Figure 2

Planned or initiated clinical trials based on EVs. Diagrams representing the proportion of clinical trials targeting a group of diseases (A) or using a specific EV source (as biomarker or therapeutic); (B). These diagrams were obtained following a database search on the Clinicaltrial.gov website with indicated search terms (exosomes, extracellular vesicles, microvesicles). The majority of clinical trials use EVs as biomarkers from the blood or urine.

Figure 3

Disease-specific regenerative medicine strategy: toward tailored approaches. (A) Source material, mode of delivery and advantages of EV and hPSC-based therapies. (B) Therapeutic effects of EVs and cell therapies in preclinical animal models for selected organs (eye, skin, heart, skeletal muscle) and expected cumulative effects.