Stem cells are versatile, progenitor cells capable of differentiating into various cell types with potency decreasing from totipotent to pluripotent, multipotent, oligopotent and unipotent cells.¹

Totipotent cells possess the largest differentiation potential, while pluripotent stem cells (e.g., embryonic and induced) give rise to cells of all germ layers but not extraembryonic structures. Multipotent and oligopotent stem cells differentiate into discrete cell lineages.

Overview of the different types of stem cells

Embryonic stem cells (ESCs)

Definition

Embryonic stem cells are pluripotent, capable of differentiating into various cell types, and are derived from early-stage embryos.²

Characteristics of embryonic stem cells

ESCs are derived from the inner cell mass of embryos and possess the unique ability to differentiate into any cell type in the human body. ESCs also exhibit self-renewal capacity, allowing them to replicate and maintain their undifferentiated state for prolonged periods in culture.

Significance in drug discovery

The utilization of embryonic stem cells in drug discovery holds the potential to generate diverse models of adult cells for primary screens, secondary pharmacology, safety evaluation, metabolic profiling and toxicity assessment.

Types of embryonic stem cells

Totipotent stem cells

Totipotent stem cells are a type of undifferentiated cell with the remarkable ability to give rise to all cell types necessary for the development of a complete organism.

These cells have the widest developmental potential and can differentiate into any cell type in the body, as well as supporting structures such as the placenta and other extraembryonic tissues.

Pluripotent embryonic stem cells

Pluripotent embryonic stem cells are undifferentiated cells derived from the inner cell mass of embryos.

They possess the unique ability to differentiate into cells of all three germ layers—endoderm, mesoderm and ectoderm—enabling them to potentially generate any cell type in the human body.³

Applications and challenges

• ESCs have the ability to differentiate into various cell types, making them promising candidates for regenerating damaged tissues and organs.⁴
• The pluripotent nature of ESCs can be leveraged to develop cell-based therapies to treat various diseases.
• ESCs offer the potential to generate tissues and organs for transplantation, addressing the shortage of donor organs.
• A major obstacle lies in the ethical quandary of utilizing human embryos to extract embryonic stem cells. Furthermore, the prospect of teratoma development and the risk of immune rejection following transplantation represent substantial challenges.⁵'⁶ Furthermore, the development of laboratory-grown organs for transplantation has yet to come to fruition.

Adult (somatic) Stem Cells

Adult stem cells, characterized by their ability to differentiate into specific cell types, self-renew and exhibit tissue-specificity, are crucial for regenerative medicine. With lower tumorigenicity compared to embryonic stem cells, they offer a safer option for autologous therapeutic use.⁷

Significance in drug discovery

In drug discovery, adult stem cells serve as valuable tools for disease modeling, drug testing and personalized medicine approaches. Their significance lies in advancing our understanding of diseases and developing targeted therapies with enhanced efficacy and safety profiles.

Types of adult stem cells

Hematopoietic stem cells

Hematopoietic stem cells (HSCs) are multipotent cells with the ability to differentiate into diverse blood cell types, encompassing both myeloid-lineage and lymphoid-lineage cells. As the primary source of blood cell production, HSCs play a pivotal role in maintaining the body's hematopoietic system. Their capacity to give rise to red blood cells, white blood cells and platelets makes them essential for sustaining immune function and ensuring proper oxygen transport within the circulatory system.⁸

HSCs find crucial clinical applications in stem cell transplantation. Hematopoietic stem cell transplantation (HSCT) involves infusing autologous or allogeneic stem cells to restore a functional hematopoietic system in patients with blood disorders. With 53% being autologous and 47% allogeneic, HSCT has shown significant long-term success, especially in treating conditions like acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma and Hodgkin disease.⁸

Mesenchymal stem cells

Multipotent stromal cells, commonly referred to as mesenchymal stem cells (MSCs), can be found in various tissues, including bone marrow, adipose tissue, umbilical cord and dental pulp. They originate from mesoderm during embryonic development. MSCs are characterized by their capacity to differentiate into multiple types of cells, such as osteoblasts (bone cells), chondrocytes (cartilage cells), adipocytes (fat cells) and other connective tissue cells. This differentiation potential makes MSCs a valuable resource for regenerative medicine.

MSCs exhibit diverse therapeutic roles, notably in immunomodulation, tissue regeneration and pathogen modulation. While they hold promise for conditions like liver fibrosis and tuberculosis infection, further research is needed to elucidate their direct contributions in clinical settings.⁹

Neural stem cells

Neural stem cells (NSCs) are the primary source of new neurons and glial cells in the central nervous system. Their ability to differentiate into various neural cell types plays a crucial role in neurodevelopment, maintenance and repair, contributing to the overall function and plasticity of the nervous system.

Due to the adult brain's limited regenerative capacity, NSCs present novel avenues for treating refractory neurological diseases, including neurodegenerative disorders and stroke. Targeted differentiation of NSCs into specific neural cell types offers potential therapeutic strategies for conditions like Parkinson's disease and ischemic stroke.¹⁰

Epithelial stem cells

Epithelial stem cells play a pivotal role in preserving and restoring diverse tissues. Their responsibility includes the effective regeneration and repair of the intestinal epithelial lining. Recent research indicates that the capacity of epithelial stem cells can vary based on whether they are engaged in regular tissue maintenance, healing a wound or forming new tissue following transplantation.¹¹ Moreover, indications of regulatory niches for epithelial stem cells in the lung emphasize their significance in maintaining lung equilibrium and facilitating repair processes.¹²'¹³

Induced pluripotent stem cells

Definition

Induced pluripotent stem cells (iPSCs) are created from somatic or differentiated cells through cellular reprogramming. iPSCs can differentiate into various cell types found in the body and exhibit pluripotency, resembling embryonic stem cells in their developmental potential.

Embryonic stem cell-like iPSCs

Research has shown that iPSCs share many key properties with embryonic stem cells, including morphology, pluripotency and self-renewal, indicating their potential for use in regenerative medicine and new drug screening.¹⁴'¹⁵

iPSCs present a hopeful prospect for cell replacement therapy without the ethical considerations of ESCs. Furthermore, iPSCs derived from patients can undergo differentiation into cell types associated with diseases, serving as valuable tools for drug screening.

Tissue-specific iPSCs are obtained through reprogramming somatic cells. The origin and distinct features of tissue-specific iPSCs significantly impact their utility, with research indicating that these cells maintain an epigenetic status associated with their original tissue, affecting their differentiation potential.¹⁶'¹⁷

The epigenetic imprint retained by iPSCs can influence their ability to differentiate into cell lineages, rendering them apt for disease modeling.¹⁸ Additionally, applying tissue-specific iPSCs in regenerative medicine showcases their tissue regeneration and engineering capacity.¹⁹

Significance in drug discovery

The introduction of iPSCs has generated significant enthusiasm for creating novel models of human disease, advancing drug discovery platforms, and expanding the utilization of autologous cell-based therapies.

Applications in Disease Modeling

Emphasis has been placed on microphysiological systems to better emulate the diverse cellular ecosystems of complex tissues in studying a wide range of human diseases, including infectious diseases, genetic disorders and cancer.

Perinatal stem cells

Characteristics

Perinatal stem cells are an intermediate cell type that fuses characteristics from adult stem cells and embryonic stem cells, showcasing multipotent plasticity.²⁰

Significance in drug discovery

Perinatal-derived cells are gaining attention in drug discovery due to their potential as a source of multipotent stromal cells, stem cells, and cellular soluble mediators, offering promising avenues for developing regenerative therapies. These cells hold particular relevance in addressing diseases with limited therapeutic options, especially in fields like musculoskeletal disorders, wound healing, and respiratory conditions, where ongoing clinical trials are exploring their efficacy in diverse medical indications.²¹

Types of perinatal stem cells

Umbilical cord blood stem cells

Umbilical cord blood (UCB) is a valuable source of hematopoietic stem/progenitor cells (HSPC) and mesenchymal stromal cells (MSCs). HSPCs from UCB are used clinically for treating hematological disorders, offering advantages like easy collection and lower graft-versus-host disease risk. UCB also contains MSC-like cells with differentiation potential. Furthermore, MSCs from Wharton's Jelly (UC-MSC) display high proliferation and pluripotency, making them versatile for various therapeutic applications.²²

Placental stem cells

Placental stem cells come in various types, such as amniotic epithelial cells, amniotic mesenchymal stromal cells and chorionic plate-derived mesenchymal stromal cells, each possessing distinct characteristics.

These cells show promise in diverse applications, from research endeavors exploring their regenerative potential to medical applications, including treatments for conditions such as cardiovascular diseases, neurological disorders and tissue injuries.²³

Cancer stem cells

Definition

Cancer stem cells (CSCs) were initially identified in acute myeloid leukemia and later in solid tumors like breast and brain cancer. These cells are defined by specific surface markers such as CD44, CD24, CD29, CD90, CD133, ESA, and ALDH1, with tissue-specific variations.²⁴

Characteristics

CSCs exhibit self-renewal and differentiation abilities, though their origin is debated. Theories suggest that they arise from normal stem/progenitor cells or undergo epithelial-mesenchymal transition (EMT) to acquire stem-like characteristics and malignancy.

Tumor-initiating Cells

Tumor-initiating cells, also known as cancer stem cells, possess the ability to initiate and sustain tumor growth. These cells are characterized by their self-renewal capabilities and play a critical role in tumor development and progression. The hypothesis of cancer being driven by tumor-initiating cells, or cancer stem cells, is gaining attention as a potential novel target for treating various malignancies. Given these cells' resistance to conventional therapies, this hypothesis prompts ongoing efforts to develop specific therapeutic strategies against them.

Significance in drug discovery and cancer treatment

Identifying and targeting CSCs and their associated signaling pathways have become crucial in drug discovery and development for cancer therapy. By focusing on aberrant activation of pathways like Wnt, Notch, and Hedgehog, researchers aim to develop multitarget inhibitors to overcome CSC drug resistance.²⁵

Challenges in stem cell research

Ethical considerations

The ethical implications of stem cell research are multifaceted, primarily revolving around concerns related to the potential risks, side effects, safety, and therapeutic value associated with developing and applying stem cell-based therapies. There is ongoing debate about the ethical considerations surrounding the use of embryonic stem cells because their extraction involves the destruction of human embryos, raising ethical concerns about the sanctity of human life. Additionally, the need for rigorous oversight to ensure the safety of stem cell therapies, potential exploitation in for-profit ventures, and equitable access to emerging treatments further underscores the complex ethical landscape of stem cell research. Balancing scientific progress with ethical principles remains a critical challenge in navigating the ethical dimensions of this field.

Overcoming challenges

In stem cell research and therapy, addressing technical challenges such as efficient cell reprogramming, precise differentiation protocols, and optimization of culture conditions is essential for harnessing therapeutic potential. Concurrently, tackling biological challenges, including issues like immune rejection, tumorigenicity and ensuring the functionality of differentiated cells, is crucial to developing safe and effective stem cell-based treatments.

Conclusion

Stem cells enable multiple research avenues like personalized therapies. Ensuring the ethical and safe development of stem cell therapy is crucial, as is addressing challenges such as understanding stem cell mechanisms and improving differentiation efficiency. Despite hurdles, stem cells offer the potential for advances in medical treatment.

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