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Stem Cells: from Embryonic Origin to Induced Pluripotency – An Overview

Hartmut Pohl
Tags: Stem Cells

Stem cells are wonders of the formation and regeneration of life and form the building blocks of multicellular life on Earth. The origin of the term “stem cell” has been lost over time but it is often claimed to have originated from plant cells, frequently located in the stem of a plant at the leaf axil, that are capable of (re-)generating an entire new plant. The first appearances of the term “stem cell” in the cell biological literature dates back to the works of the German biologist Ernst Haeckel in the mid-19th century. He first named the presumed unicellular organism at the stem of the phylogenetic trees that was the putative ancestor of all multicellular life as “Stammzelle” (German for stem cell), and later used the same term in one of his characteristic leaps from evolution to embryology to describe the fertilized egg, the cell that an organism stems from. Later, at the turn of the 20th century, the term became popular to describe the common ancestral cell capable of establishing and replenishing the entire hematopoietic system, the hematopoietic stem cell, which can give rise to all cells within the blood system. Various tissue-specific stem cells have been described since and stem cells come in various forms, shapes, and capacities.

Potency of Stem Cells

The two criteria that any given stem cell has to fulfill are (1) the ability of self-renewal to maintain its own population in undifferentiated state, and (2) potency, the capacity to give rise to differentiated, specialized progeny cells. While self-renewal is pretty much undisputed, the potency of a stem cell can vary greatly which is why this trait is used to classify stem cells.

Totipotent cells, sometimes also called omnipotent, can produce all embryonic cell types as well as give rise to extraembryonic structures, such as the placenta, and can construct an entire, viable organism. Totipotent cells are only found in vertebrates and many other organisms in the fertilized egg and after the few initial cell divisions in the morula.

Pluripotent stem cells are capable of generating cells from all three types of germ layers, endoderm, mesoderm and ectoderm. The can give rise to (nearly) all cell types of an organism and entire organs under the right conditions, but are incapable of generating a viable organism in its entirety.

Multipotent stem cells have the capacity to give rise to multiple different cell types, though generally of one specific organ or family of cells. The potency is generally limited to cells of one specific germ layer, often even restricted to a certain lineage of cells. They are usually capable of replenishing a substantial subset of the cell types within an organ

Oligopotent stem cells can differentiate only into a limited number of closely related cells and are already distinctly fate-committed.

Unipotent cells can still self-renew, but are incapable of producing more than one type of cell. Many researchers do not consider these type of self-renewing progenitor cells to truly be stem cells.

Pluri- and multipotent stem cells are the stem cells in the spotlight of research and clinical applications. Totipotent cells are often extremely difficult to obtain and limited in numbers. Additionally, controlling their vast potency poses its own challenges. Oligo- and unipotent cells, on the other hand, are generally too limited in their applicability due to their restricted potency.

Potency Tree of Stem Cells

Figure 1: The Potency Tree of Stem Cells.
The more developed stem cells become, and the more committed to their lineage, the lower their potential to give rise to different types of cells. A few exemplary stem cell lineages and some of their progeny are depicted.

Another feature by which different types of stem cells can be distinguished is their origin. Developmental stem cells appear during embryonal development, while adult stem cells are residual, tissue-specific stem cells that preserve their regenerative potential through most of adulthood.

Adult Stem Cells

While adult stem cells generally have lower potency, their therapeutic potential is nonetheless remarkable. A vast plethora of drug-based therapies aimed at improving tissue regeneration are trying to foster tissue-residual stem cells to more efficiently repair tissue damage. Additionally, these cells often offer significant advantages for in vitro approaches: they are relatively easily available, require little to no in vitro processing and by being already quite committed to their lineage, they often spontaneously build the needed cells for tissue repair with little to no pharmaceutical influence.

One of the earliest and most frequently used stem cell therapies is bone marrow transplantation to reconstitute the hematopoietic system in leukemia. Another remarkable example of a useful stem cell with limited potency is the epidermal stem cell. Its sole function is to produce epidermal cells and regenerate the skin continuously. Its efficacy in fulfilling this role is outstanding and offers ample potential for applications in a broad spectrum of regenerative and transplantation applications: from relatively simple skin biopsies expanded in cell culture for burn injuries to more complex pairing of biomaterials with stem cells for efficient wound healing or a recent case where the entire skin of a boy with junctional epidermolysis bullosa had been replaced with the use of his own stem cells after transgenic correction of the disease-causing gene mutation.

These examples highlight the usefulness of adult stem cells despite their generally limited potency. However, for combatting many diseases and conditions, tissue-specific stem cells are not readily available or utilizable. In these cases, the spotlight turns onto pluripotent stem cells and how to mold them into the needed cell type. While pluripotent stem cells are the most desirable due to their vast potential to produce nearly any given cell type, they are far less easy to obtain and to tame.

Embryonic Stem Cells

One major source of pluripotent stem cells are Embryonic Stem (ES) cells, generally salvaged from excess embryos generated for in vitro fertilization. These represent the first major caveat of ES cells. The nature of their origin raises many ethical concerns and the differentiated cells obtained from ES cells are inevitably of allogenic origin causing a multitude of complications of allograft immunocompatibility.

Embryonic Stem Cells vs. Induced Pluripotent Stem Cells

Figure 2: Embryonic Stem Cells vs. Induced Pluripotent Stem Cells.
Despite their vastly different origin, ES cells and iPS cells can fulfil very similar functions in research and therapeutic applications due to their pluripotency.
ES cells are obtained from the blastocyst stage of embryonic development. The blastocyst’s inner cell mass, which would go on to form the later organism, is dissected and dissociated. The ES cell population is then expanded in cell culture and afterwards differentiated into the target cell type. And herein lies the vast complexity of pluripotent stem cells for regenerative medicine and the main reason for the immense research effort being focused on pluripotent stem cells besides their ample potential.

Obtaining the right somatic cell type out of very early, undifferentiated cells often requires complex signaling cascades and multiple differentiation steps, which are very difficult to mimic exactly in cell culture. The problem is further exacerbated by an often drastic lack of knowledge of the details by which embryonic development of adult somatic cells is achieved in its entirety. Developing cell culture and differentiation protocols to obtain therapeutic target cells out of pluripotent stem cells, all the while avoiding unwanted differentiation that could lead to unwanted side effects, such as teratoma formation, therefore requires tremendous research efforts that can take decades. This is one of the main reasons why, despite extensive stem cell research, only few stem cell therapies are currently used in standard clinical practices.

Induced Pluripotent Stem Cells

The upcoming success of stem cell therapies has further been fueled by a new type of stem cell, the induced pluripotent stem (iPS) cell. Based on the groundbreaking work of Shina Yamanaka, iPS cells are generated by genetic reprogramming of adult, somatic fully differentiated cells, unlike the previously mentioned naturally occurring stem cells. While quite a few subtly different methods have been developed to reprogram somatic cells into undifferentiated, proliferative iPS cells, they all have the use of relatively few transcription factors in common, nearly always including Oct4 and Sox2, to force cells back into an undifferentiated state. How the process of genetic reprogramming is actually occurring has yet to be understood.

Undeniably, iPS cells opened a road to stem cell therapies that had been traditionally barred: using easy to obtain patients’ tissue samples to generate stem cells. Autologous stem cell therapy with pluripotent stem cells seemed within immediate reach. However, more than a decade later, extremely few iPS-based cell therapies have made it into clinical practices or even trials.

The individual origin and reprogramming process pose additional challenges in obtaining the desired differentiated cell type and add another level of complexity to the process as compared to ES cells. First, genetic reprogramming of adult, somatic cells is painfully inefficient and only a very small proportion of cells are generally transformed into iPS cells successfully. Furthermore, fully differentiated cells are epigenetically imprinted and these epigenetic pattern might vary strongly with the source of cells, thereby influencing the behavior of the iPS cells and their progeny. Thus normalizing the generation of iPS cells poses great challenges and their pluripotent potential is not yet on par with ES cells.

These challenges can be turned into benefits, though, when it comes to researching diseases. Patient iPS cells can be used for manifold purposes, from a source of impaired cells for basic research aiming to understand the molecular and cell biological basis of a certain disease to assessing the response of individual patients to certain drugs. Other research groups have used iPS cells for organoid creation, such as mini-guts, -livers or –brains to study complex disorders manifesting in the interplay between various cell types. The list of disease-related discoveries based on iPS cell methods is growing rapidly.

Despite obstacles that still need to be overcome, few people doubt that stem cells and especially iPS cells pose the potential to change regenerative medicine forever.

Stem Cells at Enzo

Enzo Life Sciences offers a comprehensive Stem Cell research portfolio. At Enzo, we believe in providing scientists with novel tools that will help stem cell discovery. We have our SCREEN- WELL® Stem Cell Library, a collection of 130 compounds that can be used for stem cell signaling research and drug screening. We also offer a broad range of antibodies for use in all areas of stem cell research, including very efficient antibodies against the Yamanaka factors Oct3/4 or c-Myc. Every antibody is backed by our Worry-Free Antibody Trial program, allowing you to evaluate any of our antibodies of interest for your specific application or species without risk. Furthermore, our protein portfolio encompasses a variety of growth factors to differentiate your choice of cells. Please check out our Stem Cell platform for more information or contact our Technical support team for future assistance.

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