The Emerging Field of Regenerative Medicine
Regenerative medicine is the fastest growing and most dynamic field to evolve out of the contemporary allopathic method of medicine. The current trajectory of medical evolution is unprecedented in our history and regenerative medicine is the driving influence guiding our advancements. But what is regenerative medicine?
In this three-part editorial, a basic introduction for physicians interested in learning more about this field since many believe in representing the future of personalized, precision medicine in the United States. In part one, terminology and basic concepts will be introduced along with the basic concepts of regenerative medicine, with an introduction to stem cells and how the human body can be stimulated to repair itself after receiving regenerative therapies.
On the Origins of Regenerative Medicine
The first thing to clarify is that regenerative medicine is NOT “stem cell” therapy or tissue engineering. Stem cells are studied in the laboratory but not used without prior differentiation in the clinic (excluding BM reconstitution). Tissue engineering uses stem cells to manufacture, grow or print tissues derived from differentiated, tissue-specific stem cell populations. Regenerative medicine is the practice of using various regenerative cells, EVs, matrices and growth factors to help repair damage by activating endogenous, tissue specific stem cells and other regenerative cells within the body of a patient.
What is a Stem Cell?
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. There are different stem cell hierarchies and functions within the body and these will be discussed below. An important note is that exogenous (transplanted) stem cells are not the cells responsible for the medicinal effects we see in the practice of regenerative medicine. Indeed, most of the products used successfully in regenerative medicine do not contain stem cells at all, but rather a heterogeneous population of mature cells with potent biological activities relevant to immunomodulation and tissue repair. These transplanted cells signal (communicate) with endogenous, tissue-specific stem cells and other regenerative cells within the patient’s body to orchestrate regenerative and reparative outcomes. We already know that the human body exhibits a robust capacity to replace aged cells within organs and tissues, daily (homeostasis) and in response to injury (repair). Collectively these activities are referred to as “regeneration”. Some dynamic tissues and organs (skin, intestine, blood etc) are more “regenerative” compared to others (brain, heart) with a capacity to replace hundreds of millions of cells every hour throughout an entire lifespan. The problem we face as a species is that over time, as we age, our endogenous ability to regenerate declines from a robust and sufficient level at birth to a depleted and insufficient level, which ultimately precipitates age-related disease and death.
When an average person hears the words “stem cell” they typically think about one of the main types of stem cell in biology called embryonic stem cells (ESCs), which are isolated from the inner cell mass of a blastocyst (a multicellular product of the sperm and egg coming together). These cells are NOT used by physicians in clinical regenerative medicine (AKA cellular- or cytotherapy), rather they are a tool used in medical research and for the purposes of tissue engineering. In other words, ESCs, which if injected live into patients can form multi-cell-type tumors (teratomas) are used to understand stem cell biology in the lab or are differentiated into a terminal tissue for use in transplantation. These cells have a controversial history in science and medicine.
The stem cells we talk most about in regenerative medicine are 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. Some parts of the body are limited by the extent they can regenerate, such as the brain and the heart. Conversely, other body parts (organs and tissues) require constant and consistent regeneration, such as 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 our body, we’d have just a few hours to live. Stem cells are critical for our day-to-day survival, our response to injury and our ability to fight infection.
What makes a stem cell a stem cell?
“Potency” refers to the differentiation potential (the potential to differentiate into different cell types) of the stem cell and 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 (mesoderm, ectoderm and endoderm).
- Multipotent stem cells (including HSCs – stem cells of the blood) can differentiate into a number of cell types, but only those of a closely related family of cells.
What is cellular 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. Currently there are hundreds of clinical trials underway at clinics around the world using cellular therapies to address this issue for dozens of conditions broadly ranging from Alzheimer’s to Multiple Sclerosis to cardiovascular disease and many more. Hundreds of millions of dollars of federal and private money is being leveraged to test the efficacy of transplanting various “types” of cells into patients to support compromised endogenous cells. For more information about these trials visit https://clinicaltrials.gov.
What cells are being used in therapy?
Cellular or cytotherapy can be broadly split into two main approaches. The first relies on the body’s own regenerative cells and is known as ”autologous” cell therapy. The second utilizes cells from an unrelated adult or neonatal donor, referred to as “allo” or ”allogeneic” cell therapy. These cells are primarily obtained from umbilical tissue, which is typically discarded as medical waste following birth. This tissue can be collected by appropriate tissue banks with consent from the mother and transferred to a cGMP-compliant manufacturing laboratory for the isolation of the various regenerative components, including cells, EVs, extracellular matrix and growth factors (to be discussed in part 2).
There are currently three main sources of autologous cells for use in regenerative medicine –
1. Bone marrow, which requires extraction by drilling into bone, typically the iliac crest of the pelvis, and subsequently aspirating several milliliters of 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. The majority of the cells derived from bone marrow are hematopoietic (blood) stem cells (HSCs) and about 1 in 10,000 cells being MSCs. As patients age it becomes increasingly more difficult to harvest large number of regeneration-competent 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 generalized cells that cling to the outside of blood vessels throughout the entire body (pericytes). They modulate immune reactions, mediate angiogenesis and facilitate tissue repair. These, together with endothelial cells, epithelial cells and leukocytes (blood cells) are the cells that primarily facilitate regeneration and repair throughout the body.
2. Adipose tissue (fat) and stromal vascular fraction (SVF). This product is harvested by liposuction. Because fat is heavily vascularized (has lots of small blood vessels and capillaries) and because MSCs adhere to the outside of blood vessels, lipo can yield a large number of MSCs. That said, adipose requires rendering to extract the cells, which can damage the cells and also risks contamination from external bacterial, viral or fungal sources. This is one reason the FDA has issued warnings concerning the use of adipose-derived MSCs and SVF. 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 adipose and SVF, just like bone marrow.
3. 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 regeneration-competent 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. The primary value of this product are the concentrated platelets, which is referred to as platelet rich plasma (PRP) and generally functions as an irritant to re-engage the host immune system in repair. All autologous products suffer from the same age-related decline in efficacy.
What alternative sources of cells exist for cytotherapy?
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 cases, cells obtained from umbilical cord blood (UCB) just after birth are a practical substitute. UCB-derived cells are primarily hematopoietic stem cells or progenitors with between 1-5% Mesenchymal Signaling Cells (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 immune rejection or 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. These cells can be grown in culture to expand their numbers. However, the FDA does not currently allow the use of cultured MSCs in the US outside of an IND-approved clinical trial.
It is important to reiterate that cells used in cryotherapy products do not “cure” disease. The mechanism of action is perhaps different for each indication, but the results come from the ability of transplanted cells to interact with, and stimulate, the patient’s own regenerative cells. Cytotherapy is used by physicians to help improve symptoms, modulate the immune system, induce angiogenesis (formation of new blood vessel branching) and promote tissue regeneration. Transplanted cells, received as part of a 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. For this reason, older patients or those with comorbidities may respond to a lesser degree compared to a younger, relatively healthy patient. In the next part of this series, alternatives to using live cells in regenerative medicine will be discussed along with a focus on cutting out the middleman (cells) and working directly with the paracrine messages transported within extracellular vesicles and exosomes.
Dr. Ian White is an expert in the field of regenerative medicine with over 20 year’s experience in academia and industry. Dr. White is the founder, president and CSO of Neobiosis, a perinatal tissue manufacturing company, the scientific advisor to Top Doctor Magazine, and member of the Board of Directors for The American College of Regenerative Medicine.
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