Stem Cells Heal Damaged Cells by Transferring Mitochondria

An Indian team from Delhi, India has identified a protein that increases the transfer of mitochondria from mesenchymal stem cells to lung cells, thus augmenting the healing of lung cells.

Stem cells like mesenchymal stem cells from bone marrow, fat, tendons, liver, skeletal muscle, and so on secrete a host of healing molecules, but they also form bridges to other cells and export their own mitochondria to heal damaged cells. Mitochondria are the structures inside cells that make energy. Damaged cells can have serious energy deficiencies and mitochondrial transfer ameliorates such problems (see Cárdenes N et al, Respiration. 2013;85(4):267-78).

This present work from the laboratory of Anurag Agrawal, who is housed in the Centre of Excellence in Asthma & Lung Disease, at the CSIR‐Institute of Genomics and Integrative Biology in Delhi, India has identified a protein called Miro1 that regulates the transfer of mitochondria to recipient cells.

Mitochondrial transfer has so many distinct benefits that stem cell scientists hope to engineer stem cells to transfer more of their mitochondria to damaged cells, and Miro1 might be a target for such stem cell engineering experiments.

Mitochondrial transfer between stem cells and other cells occurs by means of tunneling nanotubes, which are thread-like structures formed from the plasma membranes of cells that form bridges between different cell types. Under stressful conditions, the number of these nanotubes increases.

In the present study. stem cells engineered to express more Miro1 protein transferred mitochondria more efficiently than control stem cells. When used in mice with damaged lungs and airways, these Miro1-overexpressing cells were therapeutically more effective than control cells.

This study presents the first mechanistic insight into how Mesenchymal Stem Cells (MSC) act as mitochondrial donors during attenuation of lung inflammation and injury. Mitochondrial donation is an essential part of the MSC therapeutic effect in these models and is positively regulated by Miro1 / Rhot1 mitochondrial transport proteins.
This study presents the first mechanistic insight into how Mesenchymal Stem Cells (MSC) act as mitochondrial donors during attenuation of lung inflammation and injury. Mitochondrial donation is an essential part of the MSC therapeutic effect in these models and is positively regulated by Miro1 / Rhot1 mitochondrial transport proteins.

The hope is to use Miro1 manipulations to make better stem cell therapies for human diseases.

To summarize this work:

1. MSCs donate mitochondria to stressed epithelial cells (EC) that have malfunctioning mitochondrial.  Cytoplasmic nanotubular bridges form between the cells and Miro‐1 mediated mitochondrial transfer occurs unidirectionally from MSCs to ECs.

2. Other mesenchymal cells like smooth muscle cells and fibroblasts express Miro1 and can also donate mitochondria to ECs, but with low efficiency. ECs have very low levels of Miro1 and, as a rule, do not donate mitochondria.

3. Enhanced expression of Miro1 in mesenchymal cells increases their mitochondrial donor efficiency.  Conversely, cells lacking Miro1 do not show MSC mediated mitochondrial donation.

4. Miro1‐overexpressing MSCs have enhanced therapeutic effects in three different models of allergic lung inflammation and rat poison-induced lung injury.  Conversely, Miro1‐depleted MSCs lose much of their therapeutic effect.  Miro1 overexpression in MSCs may lead to more effective stem cell therapy.

Stem Cells From Burnt Tissue May Augment Burn Treatment

Researchers from the Netherlands have discovered that cells from the non-viable tissue that remains after burn injuries, which are normally removed by debridement, to prevent infection, are a potential source of mesenchymal cells that can be used for tissue engineering. In this study, the research team of Magda Ulrich compared cells isolated from burn eschars (dry scabs or sloughs formed on the skin as a result of a burn or by the action of a corrosive or caustic substance) with fat-derived stem cells and dermal fibroblasts, and determined how well they conform to those criteria established for multipotent mesenchymal stromal cells.

According the Dr. Ulrich, who is member of the Association of Dutch Burn Centers in the Netherlands: “In this study we used mouse models to investigate whether eschar-derived cells fulfill all the criteria for multipotent mesenchymal stromal cells as formulated by the International Society for Cellular Therapy (ISCT). The study also assessed the differentiation potential of MSCs isolated from normal skin tissue and adipose tissue and compared them to cells derived from burn eschar.”

Burn treatment advances have increased the percentage of patients who survive severe burn injuries. This growing survival rate has also increased the number of people who are left with burn scars, and these scars cause skin problems, such as contracture (shortening and hardening of muscles, tendons, or other tissues that leads to deformity and rigidity of joints), and the social and psychological aspects of disfigurement.

Tissue engineering attempts to rebuild the skin are some of the most promising approaches to addressing these problems. Unfortunately, two shortcomings with this approach include finding a viable source of stem cells for the therapy and designing the scaffold that produces a suitable microenvironment to guide the stem cells toward those behaviors that engender tissue regeneration.

“The choice of cells for skin tissue engineering is vital to the outcome of the healing process,” Ulrich said. “This study used mouse models and eschar tissues excised between 11 and 26 days after burn injury. The delay allowed time for partial thickness burns to heal, a process that is a regular treatment option in the Netherlands and rest of Europe.”

Since elevated levels of MSCs have been detected in the blood of burn victims, Ulrich and her co-workers suspected that shortly after being burned, the severely damaged tissues attract stem cells from the surrounding tissues,.

“MSCs can only be beneficial to tissue regeneration if they differentiate into types locally required in the wound environment,” Ulrich said. “We concluded that eschar-derived MSCs represent a population of multipotent stem cells. The origin of the cells remains unclear, but their resemblance to adipose-derived stem cells could be cause for speculation that in deep burns the subcutaneous adipose tissue might be an important stem cell source for wound healing.”

Further work is needed to properly identify the origins of the stem cells found in the burn eschar, and how their function is influenced by the wound environment.