Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method

ABSTRACT

Introduction

Mesenchymal stromal cells (MSCs; AKA mesenchymal stem cells) stimulate healing and reduce inflammation. Promising therapeutic responses are seen in many late-phase clinical trials, but others have not satisfied their primary endpoints, making translation of MSCs into clinical practice difficult. These inconsistencies may be related to the route of MSC delivery, lack of product optimization, or varying background therapies received in clinical trials over time.

Areas covered

Here we discuss the different routes of MSC delivery, highlighting the proposed mechanism(s) of therapeutic action as well as potential safety concerns. PubMed search criteria used: MSC plus: local administration; routes of administration; delivery methods; mechanism of action; therapy in different diseases.

Expert Opinion

Direct injection of MSCs using a controlled local delivery approach appears to have benefits in certain disease states, but further studies are required to make definitive conclusions regarding the superiority of one delivery method over another.

KEYWORDS:

• Local Injection
• Mechanism of Action
• Mesenchymal Stem Cells
• Mscs

Article highlights

• It is essential to determine the delivery route and dosing of cell therapy for optimal clinical translation, given the important influences on the distribution, retention, and survival of the administered cells.

• Local administration of mesenchymal stromal cells (MSCs) into target tissues has important advantages, including rapid and localized reaction. Cells can be administered into a precise, targeted location, increasing the chance of engraftment and/or local paracrine activity, which has the potential to prolong and/or enhance therapeutic potential.

• The mechanism of action of MSCs can be attributed to secretion of paracrine factors, including extracellular vesicles and cytokines, transfer of mitochondria to nearby cells via hetero-cellular coupling, and modification of immune responses.

• Local, rather than systemic, transplantation of MSCs influences the paracrine potency in the production of trophic factors. Certain paracrine signals are transmitted over short distances, thereby producing local effects, and the crosstalk between the local microenvironment of injured host tissues and MSCs activates MSC production of cytoprotective paracrine factors.

• Biomaterials, cell pre-conditioning, priming, and genetic modifications represent promising approaches for improving therapeutic efficacy following local administration of MSCs in the treatment of a wide variety of diseases.

• Local injections of MSCs have been tested for specific diseases including those affecting the cardiovascular, neurologic, orthopedic, dermatologic, and gastroenterologic systems.

• Systemic MSC infusions have been tested in numerous settings including but not limited to aging frailty, Alzheimer’s disease, COVID-19, idiopathic pulmonary fibrosis, and congestive heart failure.

Declaration of interests

Dr. Joshua Hare previously owned equity in Biscayne Pharmaceuticals, licensee of intellectual property used in this study. Biscayne Pharmaceuticals did not provide funding for this study. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron and holds equity in Longeveron. Dr. Hare is also the co-inventor of intellectual property licensed to Longeveron. The University of Miami is an equity owner in Longeveron, which has licensed intellectual property from the University of Miami. Longeveron did not play a role in the design, conduct, or funding of the study. Dr. Hare’s relationships are reported to the University of Miami, and an appropriate management plan is in place. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was funded by the National Institutes of Health (NIH) grant, 1R01 HL107110, and 1R01 HL13735 to JMH. JMH is also supported by NIH grants 5UM1 HL113460, 1R01 HL134558, 5R01429 CA136387, and HHSN268201600012I, Department of Defense grant W81XWH-19-PRMRP-CTA and The Lipson Family and Starr Foundations.