Exosomes are small vesicles ranging from 30-100nm in size that are found in nearly all eukaryotic fluids and facilitate a range of important cellular functions. In the early 1960s, Ernest A. McCulloch and James E. started several experiments leading to the discovery of stem cells. It was not until much later in 1987 that exosomes were first identified in a mammalian reticulocyte (red blood cell)[1] and not until 2007 that exosome-mediated transfer of mRNAs and microRNAs was identified as a “novel mechanism of genetic exchange between cells.”[2]

Today, many different types of stem cell exosomes are known to exist and are increasingly becoming recognized for their role in mediating effects that are commonly associated with stem cell therapy.

Types of Stem Cells Exosomes

In this article:

• Differences Between Types of Stem Cell Exosomes
• Induced Pluripotent Stem Cell (iPSC) Derived Exosomes
• iPSC-Derived Cellular Products
• Cynata Therapeutics’ Cymerus™ Technology
• Embryonic Stem Cell (ESC) Derived Exosomes

In recent years, a flurry of commercial activity has formed around exosome diagnostic and therapeutic products. Numerous studies indicate that stem cells release exosomes that can act as paracrine mediators by exchanging genetic details with other cells. Because exosomes reflect the properties of their source cells, there are differences between mesenchymal stem cell (MSC) and cancer stem cell (CSC) derived exosomes.

MSC-derived exosomes are likely responsible for many of the traits commonly associated with MSCs, including tissue healing, reduction of inflammation, and fibrosis. For CSC-derived exosomes, studies suggest that they act as a vehicle to deliver genetic information and produce a microenvironment that can promote cancer development and progression.

While those two categories of stem cell-derived exosomes are the most commonly studied types, other types of stem cell exosomes also exist. For example, growing attention is now being given to induced pluripotent stem cell (iPSC) derived exosomes.

Induced Pluripotent Stem Cell (iPSC) Derived Exosomes

A search on scientific publication database PubMed.gov reveals that there are now roughly 194 publications pertaining to iPSC-derived exosomes, of which 52 (27%) were published in 2021, 37 were published in 2020, and 24 were published in 2019. While the investigation into iPSC-derived exosomes was essentially non-existent prior to 2015, momentum in this area appears to be growing in recent years.

iPSC-Derived Cellular Products

Additionally, there are now several iPSC-derived cellular products being tested in human patients. RIKEN has a study underway in partnership with Kyoto University in Japan that involves iPSC-derived retinal pigment epithelium (RPE) cells being transplanted into patients with macular degeneration.

Other physician-led studies underway in Japan include exploring the safety and efficacy of iPSC-derived cellular products for Parkinson’s disease and heart failure. Additionally, CiRA of Kyoto University is moving iPSC-derived platelets toward clinical trials in humans with the goal to initiate trial activity by 2019.

If any of these clinical trials generate successful outcomes, then interest into iPSC-derived exosomes will likely increase as well.

Cynata Therapeutics’ Cymerus™ Technology

Cynata Therapeutics, an Australian company, also has an iPSC-derived MSC therapy being investigated within the UK for the treatment of GvHD. Cynata’s proprietary Cymerus™ technology utilizes induced pluripotent stem cells (iPSCs) originating from an adult donor as the starting material for generating mesenchymal angioblasts (MCAs), and subsequently, for differentiating the cells into mesenchymal stem cells (MSCs).

As a result of this technology, Cynata Therapeutics can produce limitless quantities of clinical-grade MSCs at a low cost. With this powerful manufacturing platform, Cynata Therapeutics is well-positioned to become a manufacturer of clinical-grade MSC-derived exosomes.

Interestingly, Cynata’s founder, Dr. Ian Dixon, recently formed a new company called Exopharm, which entered an exosome manufacturing partnership with RoosterBio in August 2017. RoosterBio is also a specialist in producing clinical-grade MSCs in industrial quantities.

Embryonic Stem Cell (ESC) Derived Exosomes

Embryonic stem cell (ESC) derived exosomes are a less common area of study. The ethical issues associated with studying ESCs have long limited the scientific investigation in this area. Unsurprisingly, lower rates of embryonic stem cell (ESC) research correlates with lower rates of research involving exosomes secreted by ESCs.

However, there are some noteworthy scientific publications pertaining to ESC secreted exosomes, such as those below for example.

• Embryonic Stem Cell-Derived Exosomes Attenuate Transverse Aortic Constriction Induced Heart Failure by Increasing Angiogenesis. (Pang Y, et al.; 2021). 
• 3D hESC Exosomes Enriched with miR-6766-3p Ameliorates Liver Fibrosis (Wang N, et al.; 2019).
• Exosomes Derived from Embryonic Stem Cells Inhibit Doxorubicin and Inflammation in Induced Pyroptosis in Muscle Cells (Tavakoli, et al.; 2017)
• Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction (Yao-Hua Song, et al.; 2017)
• Exosomes Derived from Embryonic Stem Cells a Potential Treatment for Cardiovascular Diseases (Yao-Hua Song, et al.; 2017)
• Isolation and Characterization of Exosome from Human Embryonic Stem Cell-Derived C-Myc-Immortalized Mesenchymal Stem Cells (Lai, et al.; 2016)
• Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction (Khan, et al.; 2015)

Other Types of Exosomes

Many other cells also secrete prolific quantities of exosomes, including:

• dendritic cells
• macrophages
• B cells
• T cells
• endothelial cells
• epithelial cells
• cancer cells

Which types of exosomes do you think have the greatest potential? Share them in the comments below.

Footnotes
[1] Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987). “Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).”. J. Biol. Chem. 262 (19): 9412–20.
[2] Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007). “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells”. Nat. Cell Biol. 9 (6): 654–9.

To learn more about this rapidly expanding market, view the “The Global Exosome Market – Market Size, Forecast, Trials and Trends, 2022.”

Exosomes are small vesicles ranging from 30-100nm in size that are found in nearly all eukaryotic fluids and facilitate a range of important cellular functions. Although exosomes were discovered more than 30 years ago, it was not until recently that the scientific community began to give credit to exosomes for a range of promising traits. [Read more…]