Author: Dr. Ian White
A stem cell is a type of cell that can proliferate (divide) to make more copies of itself or can differentiate (mature) into other types of cells within the body.
In humans, the main types of stem cells we talk about are embryonic stem cells (ESCs), which are isolated from the inner cell mass of blastocysts (a multicellular product of the sperm and egg coming together), and adult stem cells, which are tissue-specific and reside within our organs and tissues. In the developing embryo, stem cells can differentiate into all types of specialized cells. In the adult, stem cells and their immediate progeny – progenitor cells, maintain adult tissues by repairing and replacing dead or damaged cells within their local neighborhood (an exception to this are mesenchymal stem cells, which will be discussed later). Some parts of the body are limited by the extent they can regenerate, such as the brain and the heart. Conversely, other parts of the body require constant regeneration, such are the skin, blood, intestine, liver and even the epithelial layer that covers the cornea of the eye. In fact, if all stem cell activity stopped in your body, you’d have just a few hours to live. Stem cells are critical for our day-to-day survival, our injury response and our ability to fight infection.
What makes a stem cell a stem cell?
Potency. “Potency” refers to the differentiation potential (the potential to differentiate into different cell types) of the stem cell. Potency is a fundamental trait of stem cells.
- Totipotent or omnipotent stem cells can differentiate into all embryonic and extraembryonic cell types. Such cells can make a whole new person from head to toe. These cells are the result of an egg and a sperm coming together. Cells produced by the first few divisions of the fertilized egg (within the blastocyst) are totipotent. In addition, science has provided a novel source of totipotent stem cells. These cells are derived from adult keratinocytes (skin fibroblast cells) and directed back into an embryonic state using specific transcription (DNA activation) factors. These are referred to as Induced Pluripotent Stem Cells (iPSCs), but are in fact totipotent just like ESCs (well, very similar).
- Pluripotent stem cells are the descendants of totipotent cells and can differentiate into many different cell types, but not all. They are limited to one of the three germ layers.
- Multipotent stem cells, including MSCs, can differentiate into a number of cell types, but only those of a closely related family of cells.
What is stem cell therapy?
When a part of the body that has limited regenerative ability becomes damaged or sick it is unable to sufficiently activate endogenous (native) stem cells to help with repair. In this case modern medicine has come up with a potential solution. If stem cells help repair and regenerate injured tissue, would it help to add or transplant stem cells to the site of injury? Currently there are dozens of clinical trials underway at academic institutions across the country using stem cells to answer this question for conditions like alzheimer’s, multiple sclerosis and cardiovascular disease. Hundreds of millions of dollars of federal and private money is being leveraged to test the efficacy of various types of stem cells in the pursuit of regenerative therapies for otherwise hopeless diseases. For more information these trials visit https://clinicaltrials.gov.
What stem cells are being used in therapy?
Stem cell therapy can be broadly split into two main approaches. The first relies on the body’s own stem cells and is known as autologous stem cell therapy. The second utilises stem cells of an adult donor or neonatal origin, referred to as “allo” or allogeneic stem cell therapy. These cells are primarily obtained from umbilical tissue, which is typically discarded as medical waste following birth.
There are currently three sources of autologous adult stem cells in humans-
- Bone marrow, which requires extraction by drilling into bone, typically the iliac crest of the pelvis, and sucking out the marrow. This can be both painful and time consuming, but depending on the age of the patient, can yield a very large number of cells. Most of the cells from bone marrow are hematopoietic (blood) stem cells with about 1 in 10,000 cells being an MSC. As patients age it becomes increasingly more difficult to harvest large number of cells, and those which are collected have relatively short telomeres (a part of the chromosome that allows cells to keep dividing. As we age they become shorter and shorter, until they reach a point where they are too short to allow further cell division and the cell dies). MSCs are very general stem cells that cling to the outside of blood vessels throughout the entire body. They modulate immune reactions, mediated angiogenesis and facilitate tissue repair. These are the primary cells that allow regeneration and repair within the body.
- Adipose tissue (fat), also referred to as stromal vascular fraction (svf). This is harvested by liposuction. Because fat is heavily vascularized (has lots of small blood vessels) and because MSCs adhere to the outside of blood vessels, lipo can yield a large number of MSCs. That said, adipose requires rendering in order to extract the cells, which can damage the cells and also risks contamination from external bacterial, viral or fungal sources. This is one of the reasons that the FDA has issued warnings about the use of adipose-derived MSCs, particularly for non-orthopedic uses including, but not limited to, the heart, brain and eyes. Among those seeking cellular therapy, svf is a popular treatment option mainly due to the large number of clinics that offer this minimally invasive service. Issues with patient age and decreasing telomere length and regenerative efficacy are an issue with svf, just like bone marrow.
- Peripheral blood. This is collected the same way a blood donation would be collected. The erythrocytes (red blood cells, RBCs) are then separated by density gradient and the remaining mononuclear cells (white blood cells) are infused back into the patient. This method is the least invasive, but yields the fewest stem cells as the majority of cells in the periphery of an adult are hematopoietic progenitor cells (HPCs) or mature cells, with a few circulating endothelial progenitor cells (EPCs) and MSCs. Again, issues with aged telomeres reduces the regenerative ability of these cells.
What alternative sources of stem cells are there?
Harvesting tissue-specific stem cells comes with a multitude of challenges. For example, if a patient suffers from a compromised ocular (e.g. limbal) stem cell compartment it is not possible to harvest limbal stem cells from their conjunctiva and an alternative source of cells is required.
In many of these cases, stem cells are obtained from umbilical cord blood (UCB) just after birth are a practical substitute. UBC-derived cells are primarily hematopoietic progenitors with between 1-5% MSCs. These cells are naive blood cells and have not matured to express HLA or MHC. As a result, they can typically be tolerated in a wide range of patients without adverse effects. By far the best source of MSCs is the Wharton’s Jelly, which is the connective tissue within the umbilical cord itself. A typical cord can provide over 400,000 MSCs compared to 1 out of 10,000 bone marrow cells. Research is pretty clear that more MSCs results in better clinical outcome. These cells can easily be grown in culture, which would theoretically solve a lot of issues associated with harvesting these cells. Unfortunately, the FDA does not currently allow the clinical use of cultured MSCs in the US and this is forcing a greater number of American patients to seek therapy in unregulated clinics outside of the US.
What don’t stem cells do?
They don’t cure diseases. Stem cells are not a medicine. Stem cells are little sacks of protein and lipid that have the potential to migrate to sites of injury where they release growth factors that replenish, replace, fortify, activate, direct and/or educate the endogenous regenerative program to correct a chronic or acute problem that is otherwise refractory to healing/recovery. Stem cells do not “cure” a disease. The mechanism of action is perhaps different for each ailment, but the results come from the ability of the stem cells to interact with and stimulate the patient’s own cells.
What do stem cells do?
Many things. From improving symptoms to modulating the immune system to inducing angiogenesis (formation of new blood vessels) to facilitating tissue regeneration. Stem cells, received as part of the therapeutic intervention, do not engraft into the patient, but rather they communicate via paracrine (local) signaling to help drive the body’s own repair mechanisms.
What is the current status of stem cell therapy in the US?
Currently the FDA only approves a limited number of stem cell therapies. These include treatments involving bone marrow transplants for cancer and umbilical cord blood for specific blood-related disorders. There are no approved stem cell treatments for other diseases. Why is this? Despite hundreds of thousands of anecdotal cases showing positive outcomes, it is currently very difficult, and often cost prohibitive, to prove scientifically whether a treatment actually helps with any given disease. As such, billions of dollars are being spent across the medical field in clinical trials to demonstrate the efficacy of stem cells to help treat dozens of disorders ranging from alzheimer’s to cardiovascular disease. Unless federal restrictions loosen many more years and many more millions of dollars will have to be spent before stem cell treatments will receive approval by the federal government. While this is frustrating, we have to remember that the FDA is there to protect the public from deceit and injury. Because of the potential of stem cells there are many out there who would take advantage of this technology without fully understanding the medical or scientific ramifications. Hundreds of clinics are opening up across the US with little or no scientific background. Wannabe entrepreneurs open clinics and buy PhDs from non-accredited, online “universities” and refer to themselves as experts.
How can the public discern the difference between legitimate, science-based technology and charismatic charlatans? Evidence-based research. This is what the FDA is looking for. And this is why the field is moving so slow and why patients are going to locations outside the US to receive stem cells. This situation doesn’t help anyone. Moving forward we need the FDA to recognize legitimate facilities that are attempting to help the field progress and they need to facilitate this work and recognise compelling data that may not come as a result of multimillion dollar, multi-institute, double-blinded, randomised phase 1-3 clinical trials.
Dr. Ian White is a research scientist with expertise in cardiovascular biology, tissue regeneration and stem cell biology. Also experienced in immunology, biophysics, genetic medicine and Innovate approaches to frontier research in medicine. Dr. White is the Founder and CSO (Chief Science Officer) of BioFirma and also holds an adjunct position at Bascom Palmer Eye Institute where he leads the Transnational Ocular Regenerative Medicine Unit. He was recently elected to the position of Chairman of the Scientific Committee of the American Association of Stem Cell Physicians. Dr. White received a BS and MS from Liverpool University, England and went on to receive his Ph.D. from the Ansary Stem Cell Institute of Cornell University.