Can Mesenchymal Stem Cells Inject Fresh Mitochondria into Covid Damaged Lungs?

Stem cell injections have stirred the public imagination, as a way to rejuvenate the body.

Mesenchymal stems cells which are found in bone marrow and other tissues are traditionally used in the clinic setting to repair orthopedic injuries such as torn rotator cuffs. Scientists are also now looking at mesenchymal stem cells as a way to treat Acute Respiratory Distress Syndrome (ARDS).

In the case of repairing lung injury, in mice it was observed that tiny bridges (tunneling nanotubes) extend from the MSC to the damaged alveoli and transport a mitochondria, to repair the ATP function of the damaged lung tissue. In other words the stem cell is not repairing the lung by grafting to the lung tissue but rather by repairing the damaged little organelles (the mitochondria) that have lost their ability to transport oxygen and help the patient breath.

Dr. Michael Matthay is leading a University of California, San Francisco clinical trial to see if stem cell therapy can treat Covid-19 symptoms.

According to Dr. Matthay the effects of Mesenchymal stem cells, may be due to two major pathways: a no cell contact pathway, and a cell-to-cell contact dependent pathway:

Paracrine pathways – MSCs appear to release paracrine molecules that reduce injuries. For example, MSCs appear to have beneficial effects on lung injury by releasing interlukin1 antagonist, and anti-microbial peptides (as well as anti-inflammatory and growth factors for tissue repair).

Mitochondrial transfer – It also turns out that other studies suggest a cell contact dependent mechanism. At Columbia University, the team at Dr. Bhattacharya Laboratories observed that MSCs (when given directly into the air space of the lung) appear to attach to the alveolar pathway and deliver mitochondria to the injured alveoli epithelium; these alveoli appear to have mitochondria that’re injured and don’t perform normally. This “mitochondrial transfer” appears to rescue the mitochondria, restore the damage to the alveolus, and allows it to function better by restoring ATP level to normal to allow fluid transfer and surfactant release.

(ARDS) is pulmonary edema, or fluid in the lungs, not due to heart failure.   It is a condition that affects 200,000 people/year in the USA with a 30-40% mortality rate.  During ARDS, there are many cellular changes with complex pathophysiology making it extremely difficult to treat.  Currently, patients are treated by ventilation with low tidal volume and fluid conservative therapy as many pharmacological interventions have failed.  Mesenchymal stem cells (MSC), however, may hold promise as a treatment.

MSCs may be doing several therapeutic things at once – secreting signaling or paracrine factors to tell the lung tissue to repair. And making cell-to-cell contact using a tiny tunneling nanotube to transport fresh, healthy mitochondria into a damaged alveoli.

In a clinical trial allogenic (allogenic means from a different donor) bone marrow MSCs were tested on sheep with sever ARDS. Giving human MSCS to sheep with ARDS improved oxygenation, and Pulmonary edema was reduced in sheep treated with high dose of MSCs ten million cells per kilogram.

Sampling plasma in the lungs are planned in Phase 1/11 Trials in humans, to determine if the cytokine or pro-inflammatory levels change.

According to Dr. Matthay secondary endpoints may include oxygenation index, pulmonary dead space, ventilator-free days, mortality, systemic organ failure-free days, and biological markers of efficacy.

Future strategies, may even include giving patients with ARDS paracrine factors and not just the MSCs.

Paracrine signaling is science speak for a signal that is sent at close range between a cell and a nearby cell. By contrast, a chemical signal picked up by the bloodstream and taken to distant sites is called an endocrine signal. Most hormones produced in your body are endocrine signals. For example, hormones produced in the pituitary gland at the base of the brain are carried by the bloodstream to act on the adrenal glands.

Paracrine signaling is a form of cell signaling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action).

Mitochondria contain their own DNA – DNA that is simpler than our DNA but critical to respiration. Respiration depends on a dynamic equilibrium between oxidation and reduction. There are thousands of respiratory chains inside a single mitochondrion.

Since the ATP respiratory chain is embedded inside the wall of the mitochondria, by transferring mitochondria the stem cell restores respiratory function.

A little piece of bacteria inside the stem cell – was observed under electron microscope moving outside and then into the damaged piece of lung sac.

The initiating action signal seems to be coming not from DNA but involves the mitochondrial DNA in distress.

Mitochondria are similar in structure to the bacteria found in common garden soil. And yet mitochondria DNA (despite being simpler in structure than human DNA) can signal to the stem cell to do cell-to-cell contact.

The body has several different types of stem cells :

Embryonic – Embryonic stem cells come from unused embryos and are pluripotent which means that they can turn into more than one type of cell. Embryonic stem cells can develop into more than 200 cell types of the adult body.

Pluripotent – Induced pluripotent stem cells are cells that have been engineered in the lab by converting tissue-specific cells, such as skin cells into cells that behave like embryonic stem cells. iPS cells share many of the same characteristic of embryonic stem cells. The first iPS cells were produced by using viruses to insert extra copies of genes into tissue-specific cells.

Hematopoietictic – blood-forming or hematopoietic stem cells reside in the bone marrow and can give rise to red blood cells, white blood cells and platelets.

Mesenchymal – Mesenchymal stem cells (MSCs) are multipotent stem cells found in bone marrow that are important for making and repairing skeletal tissues, such as cartilage, bone and the fat inside bone marrow. 

Mesenchymal stem cells (MSCs) are sometimes called the “injury drugstore”. The body contains these stem cells in a variety of tissues all over the body, constantly repairing injuries.

Only about 0.01% of the cells in the bone marrow are MSCs. Obtaining a mixture of mesenchymal cell types from adult bone marrow, for research, is fairly easy. But isolating the tiny fraction of cells that are MSCs is more complicated.

In a healthy person, MSCs normally reside in the bone marrow in a state of quiescence.

Cellular quiescence is a dormant but reversible cellular state in which stem cells do not proliferate – but instead sit in stand by mode. Adult stem cells can be maintained in this quiescent state, and only get activated upon tissue injury to restore homeostasis. Initially it was believed—based largely on classic studies of hematopoietic SCs (HSCs)—that quiescence was an integral property of all SCs, allowing them to preserve their proliferative potential and limit DNA damage. However, the discovery of highly proliferative SCs in many tissues has challenged this notion (Clevers and Watt, 2018).

Mesenchymal stem cells, are classified as multipotent stem cells, due their capability to transdifferentiate into various lineages that develop from mesoderm. The multipotent stem cells, unlike their cousins the pluripotent stem cells, are theoretically able to differentiate to only one germ layer. (The embryo has three germ layers of cells: ectoderm, mesoderm, and endoderm.)

MSCs can be isolated from a variety of tissues, such as bone marrow, adipose tissue, placenta, umbilical cord, umbilical cord blood, liver, dental and more. MSCs can transdifferentiate to other tissues but it is assumed that most of the benefits come from the factors they secret in the target environment.

Some scientists even want to change the name of MSCs to Medicinal Signaling Cells to more accurately reflect the fact that these cells home in on sites of injury or disease and secrete bioactive factors that are immunomodulatory and regenerative. Possibly the patient’s own tissue-specific stem cells construct the new tissue as stimulated by the bioactive factors secreted by the exogenously supplied MSCs.

Stem cells can divide (keeping a copy of itself, supply of stem cells). And then using a “homing” signal, the body appears to send the stem cell circulating in the blood, like a tiny heat-seeking missile.
When tissues are damaged, MSCs are naturally released into circulation, migrate to the site of injury, and secrete molecules to create a microenvironment that promotes regeneration (Chapel et al., 2003, Caplan, 2009).

Originally, it was thought that these stem cells engrafted into the damaged tissue and differentiated into new tissue.

A new hypothesis is that it’s the “signals” (and other growth factors) that MSCs send to the damage tissue that provide beneficial effects. Upon reaching the target tissue, MSCs secrete a variety of factors with powerful immune-modulating effects.

Several laboratories are investigating the hypothesis that adult stem cells exert their therapeutic benefits via the release of biologically active proteins, or paracrine factors.

Mitochondrial DNA may play a significant role in health. Besides regulating ATP and energy production, apoptosis, damaged mitochondria may be signaling micro stem cell rescue missions.

If scientists on the front lines of Covid can figure out how mesenchymal stem can restore damaged lungs it could offer a new treatment for ARDS. And perhaps one day lead to a regenerative medicine treatment to fix damaged mitochondrial function in other diseases.