The Role of Stem Cells in Wound Healing: An Overview

The evolution of stem cells in the chronic wound regimen has taken a very circuitous path, so to speak. This article will briefly describe some of the different types of stem cells and how they may be utilized as therapeutic modalities in healthcare, including specifically in wound care.  

TYPES OF STEM CELLS

When we talk about the types of stem cells that are used in healing today, there are several. Let’s start with mesenchymal stem cells, which were first identified more than 150 years ago. Mesenchyme is bone, fat, tendon, cartilage — it’s our connective tissue. There is connective tissue that also surrounds and contains organs. Mesenchymal stem cells have been used in laboratory settings for many years, dating back to at least the late 1970s, but it wasn’t until more recently that they were used commercially. Today, we can have this type of treatment available to patients to help them heal their wounds and have a greater impact on their lives. 

There are also embryotic stem cells, which most people are very familiar with due in part to the dialogue that exists about religious implications involving their use in healthcare, and things of that nature. Scientists discovered ways to derive embryonic stem cells from murine embryos more than 30 years ago.¹ Embryotic stem cells are very potent; they’re used for the treatment of diseases in laboratory settings because they have the capability of forming teratomas, a type of proliferating cancerous growth. There have been fascinating discoveries on the use of inducible pluripotent stem cells, in which a somatic cell, such as a fibroblast, can be taken and reprogramed with a specific genetic cocktail back to that embryonic type with a significant reduction in that teratoma formation. It is astonishing, when we look at these different types of stem cells, that we are able to recover them and reprogram some of our normal body cells into inducible pluripotent stem cells — and then be able to use those in a therapeutic way. We have professionals who have been able to understand this process and be able to develop ways to make these types of cells available to be placed back into our system to treat underlying diseases while maintaining a substantial effect upon people’s longevity and quality of life. 

Stem cells can be recovered from virtually every vascularized tissue in the body, and that is because stem cells will line the walls of vessels. Mesenchymal stem cells are pericytes, which are starfish-shaped contractile cells that wrap around the endothelial cells that line the capillaries and venules throughout the body. When we have injury or inflammation, these cells can detach and flow with the blood to that site, being drawn by those pro-inflammatory mediators and secreting a curtain of different types of proteins that help protect from an overactive immune system, preventing excessive autoimmune-type functions. From the posterior side of these stem cells, they secrete a myriad of trophic factors to draw cells to the area to encourage angiogenic growth. They have incredible chemotactic and mitogenic capabilities. Mesenchymal stem cells differentiate back into the pericyte phenotype and again line the wall of the blood vessel, because the walls of the blood vessel must be stabilized before blood can start flowing through it.

STEM CELLS & WOUND CARE

Now, in the wound healing arena, we are using mesenchymal stem cells isolated from placental tissue — living cryopreserved placental membrane — a very powerful tissue in and of itself. Within the placenta, one out of every four nucleic cells is going to be a mesenchymal stem cell. And within that living amnion tissue, there is a very powerful cell, known as the amnion epithelial cell, that is robust, contains stem markers, and is more proliferative than a bone marrow-derived stem cell, according to some reports. The placenta is an amazing, complex tissue and cellular component containing thousands of different proteins and hundreds of different cellular matrix proteins. 

Still, it’s always been an interesting question: Why aren’t more people understanding these processes and then using these more robust capabilities in the wound healing arena? A lot of it goes back to using therapies in which we’re taking from aged people. For example, there are platelet-rich plasmas where you are harvesting the patient’s own blood and spinning them down, using that platelet component, and being able to put that into tissue. But why would we use tissue from an aged individual when we can take tissue from an almost neonatal-type tissue from the placenta using the myriad of cells that are unmolested by the disease process, and unmolested in and of itself, by aging? Wound care clinicians can certainly advocate for more research.

STEM CELLS, SENESCENCE, & THE AGING PROCESS

Stem cells can divide and give off a “daughter cell,” which is clinically termed as a “progenitor cell.” There are hematopoietic-type progenitor cells housed in bone marrow throughout the body; parts of our immune system also have progenitor cells, and, of course, skin and organs can produce a progenitor for a terminally differentiated cell. Those are our keratinocytes or fibroblasts — terminally differentiated cells that we do not replace. When a stem cell divides, each daughter cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.¹ But as we reach our 70s and 80s, we find one stem cell per 400,000 nucleated cells in the aging bone marrow. Additionally, as we get older our cellular capabilities decline. The cells become slower. Their secretory capabilities are reduced. They are less robust because the aging process leads to cellular senescence, a phenomenon by which normal cells cease to divide. Senescence occurs deep in the mitochondria because the inefficient transfer of electrons in the mitochondria, something known as the electron transport chain, generates these reactive oxidative species. As we get older, that continued leakage, that continued buildup — known as the free-radical theory of aging — means these reactive species will then damage the mitochondria. They then can accumulate and damage the other organelles within that tissue, particularly even the nucleus, and induce that senescence. 

Cellular senescence is a state of irreversible growth arrest, but is very metabolically active in a very pro-inflammatory way. Senescent cells secrete a myriad of different types of chemokines, cytokines, growth factors, and proteases called the senescence-associated secretary phenotype. Those inflammatory molecules can then spread and have systemic effects on the body, such as obesity-induced senescent cells that produce the chronic, sterile, low-grade inflammation that leads to the initiation of diabetes and the progression of its deleterious consequences. Think of cellular senescence as being an anti-tumor mechanism: that’s what it is designed to be. When we get damage to our telomeres — the ends of our chromosomes — that is a sign of naturally occurring aging. That is why it is more difficult to repair and regenerate as we get older, and that is why we have a heightened risk of comorbid diseases as we get older — because of the underlying inflammation. 

When considering that there could be a disease state on top of that senescence (and diabetes is probably one of the greatest examples of where premature aging of tissues is involved), the aging cells are even less robust. Make no mistake, diabetes will affect your own stem cells. So, a stem cell from someone who is living with diabetes is much less robust than a stem cell from someone who is not diabetic, even with age-matching individuals. That is why we need to take cells from that wonderful area of a placenta that protects the fetus, allows it to grow, and protects it from the mother’s immune system. The amnion and chorion have many pleiotropic capabilities; when we put these derived stem cells into a chronic deficit — the area that is diseased — we are able to repair and regenerate those tissues. Cancer is an example of cellular senescence. We tend to see cancer as an “older age” disease, and all of these pro-inflammatory components that are being secreted can affect its progression, particularly in those living with diabetes. These patients have a heightened risk for cancer development because of the pro-inflammatory environment, which leads to cancer formation due to tissue disruption, growth signals, and chronic inflammation. Ultimately then that chronic inflammation can create other age-related diseases, further affecting the patient's health. 

FUTURE OF STEM CELL EVOLUTION

We probably know 50-60% of the biological process behind the wound healing paradigm today. It is a very pleiotropic environment. At certain times, certain proteins that are produced are good, and at other times those same proteins can have a very detrimental effect on the human body and on outcomes, morbidity, and mortality. The evolution of stem cell utilization in wound care (and healthcare overall) is only going to get more intense as we start to understand the whole paradigm and as we more clearly understand how these cells work, how they interact, how they attract, how they repair, and how they regenerate. In 20-30 years, perhaps, when people are living with a chronic autoimmune disease, perhaps even diabetes, they might be getting intravenous infusions of stem cells that will home to that area of inflammation in the pancreas, to turn off that inflammation, and turn on the characteristic healing factors that we need to fix the problem. This type of treatment is not that far away. Research will remain “the cure.” 

Matthew Regulski is a partner at Ocean County Foot & Ankle Surgical Associates, P.C., Toms River, NJ, and director of the Wound Institute of Ocean County, NJ.

Reference

1. Stem cell basics. National Institutes of Health. 2018. Accessed online: https://stemcells.nih.gov/info/basics/1.htm

ONLINE EXCLUSIVE: Stem Cells & The Outpatient Wound Clinic Video Series

In this exclusive four-part video series, Matthew Regulski, DPM, ABMSP, FASPM, FAPWH(c), educates wound care clinicians and program directors on the state of stem cell utilization in the outpatient clinic today and takes an historical perspective on the evolution of stem cells and regenerative medicine within the healthcare industry.

Video 1: Mesenchymal Stem Cells & the Outpatient Wound Clinic

In this video interview, Dr. Regulski discusses the benefits and utilization of mesenchymal stem cells in the wound clinic population, paying particular attention to those living with diabetes. Reimbursement protocol is also shared. 

Video 2: The Evolution of Stem Cells & My Wound Care Practice

In this video interview, Dr. Regulski discusses the history of stem cell utilization and trials, as well as the evolving path that stems cells continue to take in the chronic wound regimen today. He also shares some personal insight as to the research that he has conducted in his practice in regard to stem cell utilization.

Video 3: Discussion on the Science & Clinical Utilization of Stem Cells

In this video interview, Dr. Regulski discusses the various types of human stem cells, including mesenchymal stem cells and embryotic stem cells, and offers some predictions on the future of regenerative medicine in wound care and healthcare.

Video 4: Stem Cells, Senescence, & the Aging Patient

In this video interview, Dr. Regulski discusses the phenomenon of cellular senescence and its impact on the human body as we age.