Since their discovery in 1981, stem cells have demonstrated promising therapeutic applications – they have persisted as a common media topic, with research efforts continuing to pick up momentum nearly 40 years later. This guide offers a quick introduction to stem cells, current stem cell research efforts, widely-used stem cell treatments, and clinical trials currently underway in 2020.

What Are Stem Cells?

The defining property of stem cells (SCs) is their capability for self-renewal, maintaining an undifferentiated state throughout numerous cycles of cell division. Although the ability to indefinitely divide is shared between both SCs and immortalized cell lines, the main difference is that SCs are a normal part of development in multicellular organisms - immortalized lines proliferate indefinitely due to mutation. The second key characteristic of SCs lies in their potency, or capacity to differentiate into specialized cells under specific conditions. Generally, the potency of SCs becomes more limited as they differentiate, under specific circumstances, over the course of organismal development.

Where Do Stem Cells Come From?

One significant misconception is that all stem cells are derived from early embryos, known as embryonic stem cells (ESCs), but there are actually multiple sources. Somatic (adult) stem cells are found in our bodies throughout our lives, and are believed to differentiate into cells limited within the tissue of residence. As multicellular organisms age, SCs help replenish the body’s supply of specialized cells which cannot replicate through division, such as blood and muscle. Several factors influence differentiation potential, including SC type, source, stage of development, physiologic/experimental conditions, and more.

Overview: Types of Stem Cells

Type

Source

Differentiation Potential

Embryonic stem cells (ESC)

Derived from the inner cell mass of the blastocyst (early pre-implantation embryo)

Pluripotent

Somatic (a.k.a. adult) stem cells

Present in multicellular organisms through lifetime - derived from bone marrow, blood, adipose tissue, and more.

Multipotent,

Oligopotent,

Unipotent (progenitor)

Induced pluripotent stem cells (iSC)

(a.k.a. reprogrammed)

Adult specialized cells are turned into embryonic-like stem cells via epigenetic reprogramming techniques.

Pluripotent,

Progenitor – multipotent or unipotent

 

A Closer Look at Stem Cell Research

Given the ethical considerations and legislative limitations involved with ESC research, recent research has typically focused on the therapeutic potential of somatic SCs. Unlike ESCs, somatic SCs have a limited ability to differentiate into specialized cell types, typically demonstrating multipotency based upon the region of derivation. The ability of somatic SCs to transdifferentiate – or produce cells of a different type – remains an important research topic in the field of regenerative medicine. There are a variety of somatic stem cell types, including mammary, hematopoietic, mesenchymal, endothelial, neural, olfactory stem cells and more. Embryonic stem cells (ESCs) are still used alongside somatic stem cells as models for the study of genetic disorders, cell cycle control mechanisms, and additional areas with clinical potential.

Somatic (Adult) Stem Cells

Mesenchymal stem cells (MSCs):

  • Differentiate into a variety of tissues/cell types: osteoblasts, adipocytes, chondroblast, hepatocytes, and more.
  • Isolated from bone marrow, adipose tissue, lung, placenta, umbilical cord, and teeth.

MSCs amplify quickly and are capable of generating a local immunosuppressive microenvironment, which contributes to their wide applications in tissue engineering, cell therapy, and gene therapy. Adipose-derived regenerative cells (ADRC), which includes MSCs, are known to modulate the inflammatory response by altering cytokine secretion of other cells. As such, there is ongoing research into how MSCs influence immune responses in the body to evaluate any therapeutic potential.

Hematopoietic stem cells (HSCs):

  • Differentiate into all blood cells via hematopoiesis.
  • Isolated from bone marrow and umbilical cord blood.

Neural stem cells (NSCs):

  • Differentiate into neurons, astrocytes, and oligodendrocytes.
  • Isolated from various regions of the adult vertebrate brain and from non-neurogenic areas such as the spinal cord.

NSCs can build functional neural circuits and have been widely studied in animal models for treating neuro-degenerative diseases, hereditary central nervous system diseases, and spinal cord injuries.

Embryonic Stem Cells (ESCs)

Unlike other stem cells, ESCs are capable of self-renewal indefinitely. Due to their plasticity and potentially unlimited capacity for self-renewal, ESC therapies have been proposed for regenerative medicine and tissue replacement. To visualize such studies, the use of ESCs with constitutively expressed GFP/RFP are valuable tools for cell tracing and additional in vitro and in vivo embryonic stem cell research.

 

Modeling Disease and Studying Development with Stem Cells

Stem cells (SCs) serve a variety of purposes across the research process, from developmental studies and biological diagnostics, all the way to target validation for drug development and cell replacement therapy.

Developmental Studies

  • SCs with fluorescent tags (e.g. GFP/RFP) may be used as markers for development and differentiation studies.
  • Cancer studies often use SCs to study genetic & molecular factors which influence cell cycle control.

Disease studies for Drug Development

  • Disease Models – SCs with natural (e.g. patient-derived) or engineered genetic expression of the disease state.
  • Improved Candidate Drug Screening – Using relevant, patient-specific stem cell models (rather than the standard commercially-available lines).

Cell Replacement Therapies

Bone marrow transplantations are the most common form of stem cell-based therapy, having been used for decades to help treat blood cancers, such as leukemia. SCs can provide a renewable source of cells for treating diseases such as Parkinson’s, stroke, heart disease, diabetes, and many more.

Stem Cell Therapy for Treating Heart Damage

SCs may offer a way to repair and/or replace damaged cardiac (heart) tissues and potentially treat damage from acute myocardial infarction (heart attack) and congestive heart failure. The human heart is made up of multiple cell types, but researchers focus on three main types for mending damaged heart tissues: cardiomyocytes, cardiac pacemaker, and endothelial cells. Cardiomyocytes can be grown in the lab from ESC sources, which “strikingly… will beat in unison in a culture dish, the same way they do in a living heart muscle.” Additional research has suggested that pluripotent SC-derived cardiomyocytes can both replace damaged tissues and release signals to improve cardiac function after heart attack.1

Meflin, a glycosylphosphatidylinositol (GPI)-anchored membrane protein, has been identified as a specific marker of mesenchymal stem cells and as a regulator of their undifferentiated state. A 2019 publication ”examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure… Data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.”2

 

Clinical Applications of Stem Cells

The most well-established stem cell treatments involve the transplantation of hematopoietic stem cells to treat disorders of the blood or immune system, and to replenish the blood after specific cancer treatments. Epithelial SCs have been used as early as the 1980s to grow skin grafts for patients with severe burns. While autologous harvesting of SCs has demonstrated the least risk and most promising therapies to-date, such clinical applications will only come after extensive lab-based cell modeling efforts that most closely replicate the target systems (such as through genetic engineering).

Autologous Somatic Stem Cells in Clinical Trials

Osteoarthritis (OA) Therapy

One promising autologous source of SCs is adipose tissue, which involves a minimally invasive extraction procedure to yield a high frequency of MSCs.

“The EU consortium ADIPOA has shown in a ‘first in man’ 2-centre Phase I safety study that intraarticular injection of a single dose of autologous [adipose-derived mesenchymal stromal cells] ASCs to the knee (18 patients, 12 month follow-up) was well-tolerated, had no adverse effects, and resulted in an improvement in pain score and functional outcome. ADIPOA-2 will build on the work of ADIPOA to deliver a large-scale clinical trial in regenerative medicine for OA. The purpose of the project is to design and implement a phase IIb study to assess the safety and efficacy of autologous (patient-derived) ACSs in the treatment of advanced OA of the knee.”4

Multiple Sclerosis (MS) Therapy

Researchers at Sheffield Teaching Hospital are currently in the final phases of clinical approval for an autologous hematopoietic stem cell therapy (AHSCT) for Multiple Sclerosis (MS). This AHSCT treatment has provided promising results for treating the relapsing remitting type of MS, but effective treatments remain to be seen for primary and secondary progressive MS.

“MIST is the first ever international large scale randomised trial into autologous [hematopoietic] stem cell transplantation (AHSCT) in relapsing remitting multiple sclerosis (MS) and has shown that the treatment stabilised the disease and improves disability in people who had experienced 2 or more relapses in the year before joining the trial.”3

 

Stem Cell Culture Products for Research

Cyagen offers a comprehensive portfolio of OriCell™ research-use stem cell lines, including ESCs and multiple lineages of somatic SCs derived from various species. We also provide a variety of culture supplements and differentiation media to support the growth and maintenance of these cells. All our products have been widely cited in high-impact journals, including Nature and PNAS.

Cyagen’s OriCell™ Stem Cell (SC) Research Products

References:

  1. Cardiac Disease - An Overview. (n.d.). Retrieved January 8, 2020, from https://www.closerlookatstemcells.org/stem-cells-medicine/heart-disease/#understand.
  2. Hara, A., Kobayashi, H., Asai, N., Saito, S., Higuchi, T., Kato, K., … Enomoto, A. (2019). Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. Circulation Research125(4), 414–430. doi: 10.1161/circresaha.119.314806
  3. MIST Trial Findings. (n.d.). Retrieved January 20, 2020, from https://www.sth.nhs.uk/autologous-haematopoietic-stem-cell-transplantation-for-multiple-sclerosis/
  4. The Project - ADIPOA-2. (n.d.). Retrieved January 20, 2020, from http://adipoa2.eu/impact/
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