About the stem cells

Stem cells are the founders of all cells in our body

Stem cells (SCs) form every organ and tissue in our body. The initial pool of SCs, formed immediately after egg fertilization, gives rise to more than 200 types of specialized cells through complex and tightly controlled processes. Throughout our lives, we continue to rely on the SCs work in case of injury, replacement of tissues and cells that are lost daily (e.g., skin, hair, blood cells), and our intestines' lining. Thus, SCs are not something artificial or created in the laboratory. Instead, they accompany us during all our lives — from fertilization to death — being an absolute physiological necessity for the body's normal functioning.

On the other hand, SCs are unique cells that differ from all other cells of the adult body by at least two key features: the ability to self-renew and the ability to give rise to specialized cell types (differentiate). Self-renewal means that SCs can produce not just two identical daughter cells during the division but also more specialized cells with the same characteristics as the mother's SC. Due to these properties, the pool of SCs is preserved throughout human life and contributes to the physiological recovery of damaged tissues and organs.

Are all stem cells the same?

Not all stem cells are the same. The main difference between the SCs is the potential for forming a different spectrum of specialized cells. The most omnipotent cell that can form the whole organism, including auxiliary structures such as the placenta, the umbilical cord, is called totipotent (from Latin "totus" — whole). Fertilized eggs (zygote) and cells formed during the first few rounds of zygote division (blastomeres) are totipotent. With the subsequent division of blastomeres, a blastocyst is formed — a hollow sphere which contains 150-200 cells inside, the so-called "inner cell mass". The cells isolated from blastocysts are embryonic stem cells (ESCs). They can form all 200+ types of adult cells, except for extraembryonic structures. ESCs are pluripotent (from Latin "plures" — many). ESCs are immortal and can be reproduced indefinitely, which allows them to be obtained in large quantities in the laboratory. Research, conducted on the ESCs, is important for understanding the early phases of human development and molecular mechanisms of the disease pathogenesis.

SCs with pluripotent potential are not present in the adult body. All adult SCs (also called somatic SCs) are already somewhat specialized and can give rise to only a few types of cells within a particular tissue or organ. The SCs' ability to generate several cell types makes them multipotent (from Latin "multus" — several). A SC of an adult organism can reproduce for a long time, but it is not immortal. SCs can be found in organs that need constant renewal, such as blood, skin, intestines, and even less regenerative ones, e.g., brain.

Is it possible to produce stem cells?

One of the hottest topics in the study of SCs today is the study of induced pluripotent stem cells (iPSCs). These cells are artificially created in the laboratory from specialized human cells, such as fibroblasts, under the action of a mixture of chemical compounds. IPSCs correspond to ESCs on some characteristics, namely the ability to form all types of cells.

John B. Gurdon and Shinya Yamanaka received the Nobel Prize in Physiology and Medicine in 2012 for their discovery of iPSCs technology. The benefit from the iPSCs studies lies in obtaining a patient-specific stable cell line. It allows to study the mechanisms of a disease development (e.g. Parkinson's disease, Alzheimer's) and serves as a powerful tool for testing personalized therapy drugs. On the other hand, the use of iPSCs derivatives as drugs raises a number of concerns, including the high cost of culture technology and the presence of virus-based constructs in iPSCs.

How do stem cells change during human development?

The population of stem cells (SCs) changes with individual human development, and they can be broken into the following subtypes:
● embryonic SCs. They are pluripotent and are present only on the blastocyst stage, lasting for approximately 5 days after the fertilization, preimplantation period;● prenatal SCs — fetal SCs, pluripotent, mostly neural crest SCs, fetal hematopoietic SCs, and precursors of the pancreatic cell;● postnatal SCs — SCs isolated from extraembryonic structures (amnion, placenta, umbilical cord) after childbirth. Postnatal SCs are multipotent;● somatic SCs — the SCs of the adult organism. They are present in the dormant state in the organs and tissues of the adult organism, e.g., hematopoietic stem cells, mesenchymal stem cells, neural crest stem cells, etc. The potential of such SCs varies from multipotent (MSC) to unipotent (endothelial precursors).

Adult stem cells

The following groups of multipotent SCs can be distinguished in an adult organism:
● hematopoietic stem cells;● mesenchymal stem cells;● neural crest-derived stem cells.

Hematopoietic stem cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to all blood cells. Bone marrow transplantation is an HSCs transplant that began in the 1950s. Today, in addition to the bone marrow, the umbilical cord blood and placenta can be a source of HSCs. Compared to bone marrow HSCs, umbilical cord blood HSCs have a greater therapeutic potential because they are "younger". Moreover, umbilical cord blood HSCs do not require strict antigen typing, and the rejection rate after transplantation is significantly lower compared to bone marrow HSCs.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multipotent stem cells that can repair connective tissue elements — bones, cartilage, fat deposits, and an essential part of the skin — the dermis. MSCs were first isolated from the bone marrow by O. Friedenstein in the 1960s as adherent cells, showing fibroblast-like morphology with clonogenic and multipotent potential for differentiation. It later became clear that almost all tissues and organs contain MSC-like cells. You can find different terminology for MSC in literature — this can be mesenchymal stromal cells or multipotent mesenchymal stem cells.
The most optimal sources for the isolation and augmentation of MSCs with subsequent use for regenerative medicine are bone marrow, adipose tissue, umbilical cord, and placenta (ethical issues and sufficient material needed for the isolation of MSCs have to be taken into account).
The therapeutic potential of MSCs can be explained by their biological properties:
● proliferative activity — MSCs multiply rapidly in vitro, allowing biotechnologists to grow these cells in numbers required for therapeutic use;● multipotency — the ability to form several cell types under the influence of appropriate stimuli and thus replace damaged cells in the body;● trophic function — the secretion of numerous growth factors that protect cells from death and stimulate resident stem cells to repair damaged organs and tissues;● homing/migration — the ability of MSCs to find their own natural niches or damaged tissues after systemic introduction into the body due to the expression of a unique set of molecules on their surfaces, including adhesion molecules, chemokine receptors, metalloproteinases, etc;● immunomodulatory function — MSCs can affect the immune system's cells, suppressing pro-inflammatory and activating anti-inflammatory ones.

Neural crest-derived multipotent stem cells

The neural crest is a temporary structure during the embryonic development of vertebrates, represented by a population of cells with unique migratory properties and the ability to differentiate. Embryonic neural crest cells undergo a process called epithelial-mesenchymal transition. It involves the exfoliation and migration of cells to several different areas of the embryo, where they generate numerous cell and tissue types, including bone, cartilage, smooth muscle, connective tissue, neurons, and glial cells of the peripheral nervous system — melanocytes.
Numerous studies have shown that stem cells with neural crest properties are identified not only during embryonic development but also in adulthood. In humans, neural crest-derived stem cells are stored in the hair follicle, skin dermis, adipose tissue, bone marrow, palate, nasal mucosa, dental pulp, etc.
Human neural crest-derived multipotent stem cells, isolated from various tissue sources, are characterized by the following biological properties:
● high level of proliferation;● high migration potential;● ability to self-renew;● expression of a unique set of signaling molecules;● rich spectrum of proteins secreted by neural crest-derived stem cells;● ability to give rise not only to adipocytes, chondrocytes, osteocytes but also to muscle cells, melanocytes, neurons, glia cells, etc;● cellular plasticity that allows neural crest-derived stem cells to structurally and functionally integrate into the damaged organ or tissue of the recipient after transplantation;● no formation of tumors in vivo.
All the above-mentioned biological properties of the neural crest-derived stem cells, together with several available sources for their isolation in the adult body, make these cells attractive candidates for the tasks of regenerative medicine, especially in the field of neurology.

Growing stem cells in the laboratory 

Growing cells in a laboratory is called cell culture. It is important to note that the laboratory is equipped with special equipment that ensures complete sterility from contamination by microorganisms or viruses. SCs, isolated from a particular tissue, can be propagated in the laboratory in a culture vessel containing a nutrient broth — culture environment (optimized for growing different types of stem cells). Most stem cells, except for hematopoietic stem cells, attach to the plastic surface of the culture plate, gradually filling its area, actively dividing. When the SC fill the surface of the vessel, they are transplanted. One round of transfer is called a passage — (P0,1,2,3 …… 10). This process can take weeks and months before the required number of cells grows. At any stage of the process, batches of cells can be frozen. To obtain specialized cell cultures from stem cells (e.g., neurons, cartilage cells, bone tissue), biotechnologists can change the chemical composition of the culture medium, change the surface of the culture plate, or modify the cells by expressing specific genes. Over the years of experiments, scientists have created some basic protocols, or "recipes", to differentiate SC into certain specific cell types.

Application of stem cells in science and medicine

Over the last few decades, the study of SCs has been very active. In 1999, the journal "Science", one of the most authoritative scientific journals, recognized the discovery of stem cells as the third most crucial event in biology after the decoding of the DNA double helix structure and the Human Genome Program. What do SCs give us?1. SC is primarily a unique tool for studying the mechanisms of embryonic development, the choice of cell fate, the mechanisms of disease development, and finding ways to overcome them.2. Cell therapy is a new innovative direction in medicine using SCs as therapeutic agents. SCs repair damaged tissues through cellular regeneration, secretion of a number of compounds, growth factors, cytokines, etc., and regulation of the microenvironment.3. Source materials for 3D printing and 3D weaving — the use of stem cells in 3D printing programs, including 3D printing of tissues/organs seeded with living cells.4. Validation of the target drug — validation of a new drug, which is expected to be effective in treating a specific disease on specialized differentiated cells obtained from the SCs in the laboratory.5. Delivery of drugs — delivery of therapeutic agents through stem cells and exosomes of stem cells.6. Toxicological screening — the use of SCs to assess the impact of drugs on biological systems.

We create awesome things

After getting into the body of a sick person, SCs realize their therapeutic potential in several ways. The first one is direct: the SC itself turns into a cell, lost by the body. The second one is indirect: SCs secrete a number of factors that regulate the behavior of surrounding cells at the site of injury, stimulating them to proliferate, differentiate, protect against death and adjust the immune system's response.
In cell therapy, SC is administered systemically (intravenously) or locally (directly to the site of injury). If the latter is pretty self-explanatory, then the first option remains unclear: how do the SCs know where the damage is? It is worth noting that SCs are not tiny naked balls — instead, they contain thousands of different molecules (receptors) on their surface. They are like molecular sense organs, thanks to which they perceive the environment they fall in and decide where to go. The ability to find the place of damage is a natural ability of the SCs, the so-called homing. When the body has a large lesion, which can't be handled by local SCs, SCs from distant places come to help on a gradient of cytokines released from damaged tissue. At the site of injury, the SCs also continue to scan the environment through their receptors, which interact with many factors and ultimately decide whether it is enough to become a "skin" cell once or whether it is necessary to involve allies to fight.