Adult/Somatic Stem Cells Introduction
Adult stem cells are undifferentiated cells that reside among differentiated cells in a tissue or organ. They have the ability to renew themselves and differentiate into specialized cell types. Not like embryonic stem cells which can become all cell types, adult stem cells are limited to differentiating into distinct cell types of their tissue of origin, and they are therefore multipotent or unipotent stem cells. The primary roles of adult stem cells are to maintain and repair the tissue in which they reside. Adult stem cells are rare and generally small in number, but they can be found in a number of various tissues of the adult organism.
The most studied are stem cell populations present in bone marrow (hematopoietic and MSCs), intestine, and skin, but there are distinct populations residing in many other organs, such as in the central nervous system, liver, mammary gland or dental tissues. The diverse adult stem cell populations exhibit distinct markers and are affected by various signaling pathways (Wnt, Notch, Shh, etc.). Stem cells in individual tissues are influenced not only by their own signaling activity, but they also react to the specific environment created by neighboring cells called the niche.
Types of Adult/Somatic Stem Cells
Hematopoietic stem cells (HSCs) are rare cells of mesodermal origin residing in the adult mammalian bone marrow which sit atop a hierarchy of progenitors that become progressively restricted to several or single lineages. True HSCs remain mostly in the quiescent state in the adult tissue, and give rise to short-term HSCs which have limited self-renewing capacity (6-8 weeks). When the short-term HSC leaves the undifferentiated self-renewing state it can become either a common myeloid progenitor (CMP) or a common lymphoid progenitor (CLP). The myeloid lineage further gives rise to erythrocytes, monocytes and macrophages, neutrophils, basophils, eosinophils, megakaryocytes/platelets, and dendritic cells. Osteoclasts also arise from hemopoietic cells of the monocyte/neutrophil lineage. The lymphoid lineage produces T- and B-lymphocytes and Natural Killer cells.
Figure 1. Simplified diagram of differentiation of hematopoietic stem cells
The majority of mesenchymal stem cells (MSCs) reside in bone marrow stroma. The MSCs from bone marrow possess the natural ability to differentiate into mesodermal tissues such as muscle, tendon, adipocyte, osteocyte, and chondrocyte lineages. MSCs have been found in adipose tissue, intestinal stroma, eye corneal limbal stroma, trachea, and dental pulp. In these tissues, MSCs are mainly localized in niches located at the pericyte area of capillaries. Another important medical source of MSCs are neonatal tissues such as placenta, cord blood, and Wharton’s jelly. MSCs are incorporated in the regenerative processes of adult tissues, for example in the heart after infarction. MSCs may directly differentiate into particular cells from damaged tissues, and also serve as paracrine regulators of healing processes.
The intestinal stem cells (ISCs) are multipotent stem cells that can generate all kinds of differentiated cell types of the small intestine and the colon (including the predominant enterocytes (the absorptive cells); the mucus-secreting Goblet cells; the peptide hormone secreting enteroendocrine cells and the Paneth cells.).
The neural stem cell or neural progenitor cells are located in two distinct regions of brain. One population is located in the ventricular-subventricular zone in lateral ventricles. The mouse model suggested that this population is mainly responsible for renewal of neurons in the olfactory bulb. The second population is seated in the interface of the hilus and dentate gyrus of hippocampus.
The skin is divided into the dermis and the epidermis. The epidermis has stem cells that are responsible for repair and maintenance of the epithelial barrier, which turns over every 2-4 weeks. The dermis consists of connective tissue, and is the location of hair follicles, sweat glands, and blood vessels.
Epidermal Stem Cells
The epidermis begins at the most basal layer of the dermis, termed the stratum basale. This layer contains epidermal stem cells that give rise to the rest of the epidermis, which differentiate as they move upwards away from the dermis. The continual turnover of the epidermis is mediated by epidermal proliferative units, which consist of a stem cell in the stratum basale and several transit amplifying cells.
Hair Follicle Stem Cells
The hair follicle produces the hair shaft during the growth phase, termed anagen, followed by a period of apoptosis termed catagen, and remains quiescent during the resting phase, termed telogen. These processes are accomplished by a number of hair follicle stem cell (HFSC).
Sebaceous Gland Stem Cells
B lymphoctye-induced maturation protein 1(Blimp1)+ cells are unipotent stem cells that give rise to the sebaceous gland.
The dermal papilla is a population of mesenchymal cells that reside just under the hair follicle. Several studies have suggested that during hair growth, the stem cells of the hair follicle are in close proximity to the dermal papilla, and signaling molecules including Wnts, BMPs, noggin, and FGFs from the dermal papilla activate HFSCs to begin proliferating.
6. Other Adult Stem Cell Populations
The liverhas a remarkable regenerative capacity. Following acute liver injury, the tissue mass is restored by mitotic division of mature hepatocytes. However, during massive or chronic injury the hepatocyte proliferation becomes compromised and facultative hepatic progenitors are activated. These cells are bipotent and can give rise to both hepatocytes and biliary epithelia.
The mammary glandis composed of epithelial cells and mesenchymal cells, including fibroblasts, adipocytes, blood vessel cells, and immune cells. The mammary gland cells have the ability to clonally expand during morphogenesis and adult life, as well as to undergo massive expansion during several cycles of pregnancy.
Human dental tissuedoes not possess self-renewing capacity, however, there are several species whose teeth can continuously grow or are constantly replaced during the adult life. In mammals, several examples can be found within the rodent order, e.g., in mice, adult incisors contain a stem cell niche and therefore can grow indefinitely, and in others, such as voles, the stem cells reside not only in the incisor, but also in the molars. The rodent tooth stem cells are widely studied because they represent a potential entrée into dental regenerative medicine.
Special types of stem cells reside in the adult organism but do not cover all the classical attributes of adult stem cells, including germline stem cellsfound in the ovarian epithelium and testis. Male germline cells are a population of progenitor cells (known as spermatogonial progenitor cells or SPCs) that are required for life-long production of differentiating germ cells and spermatozoa. These germline cells can be converted into pluripotent stem cells, known as germline-derived pluripotent stem (gPS) cells or multipotent adult germline stem cells (maGSCs). The properties of maGSCs are similar to ESCs. They are able to spontaneously differentiate into cells forming all three germ layers and germ cells, contribute to the development of various organs when injected into an early blastocyst.
Clinical Significance of Adult Stem Cells
Adult stem cells have been used in the clinic for decades in the treatment of blood diseases. Transplantation of hematopoietic stem cellsis an established therapy, including transplants from bone marrow, peripheral blood, and cord blood. Stem cells are obtained typically from the iliac part of the pelvic bone with a syringe. This approach is now being replaced by the use of peripheral blood as a source. Only a small number of stem and progenitor cells circulate in the bloodstream normally, but greater numbers can be obtained by injecting the donor with a hematopoietic growth factor, such as granulocyte-colony stimulating factor (G-CSF), which results in a much less invasive procedure for the donor. Cord blood is another alternative source of the HSCs that can be obtained from the umbilical cord and placenta after birth.
Another type of adult stem cell that is auspicious for clinical use is the neural stem cell. Animal studies revealed the potential of neural stem cells to act protectively in the treatment of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), and this application is being clinically tested. Neural stem cells are also promising for severe spinal cord injury, as they are able to support the functional regeneration of the spinal cord. Neural stem cell transplantation is also being considered for future clinical use as a regenerative strategy after stroke to replace lost neurons. The combination of neural stem cells with hematopoietic stem cells may improve functional outcome after ischemic brain lesions.
T1DM, Heart Attack, Pulmonary Disease and Oral Disease
MSCs can protect human islets, which could potentially be a therapy for type 1 diabetes mellitus (T1DM). Possible applications for MSCs also include treatments for heart attack, as well as pulmonary disease. Because MSCs have been identified in several oral and maxillofacial tissues, MSCs represent a promising source in the dentistry field. These findings support the possibility to use MSCs in innovative technologies for tissue engineering strategies to regenerate or replace damaged, diseased or missing oral tissues.
Prospect Research of Adult Stem Cells
Adult stem cells (ASCs) are found in many of the major adult organs and are essential for tissue homeostasis as well as regeneration in response to injury. ASCs appear to be regulated by intrinsic and extrinsic mechanisms. ASCs are intrinsically distinguished from their progeny on the basis of epigenetic, transcriptional, and potentially metabolic modes of regulation. Dysregulation of these intrinsic factors such as the introduction of oncogenic mutations can result in cancer initiation. Moreover, the extrinsic environment in which ASCs reside also regulates their identity and activity. ASCs live in specialized niches, which interacts with ASCs through sending and receiving signals, such as growth factor signaling, extracellular matrix association, and mechanical regulation. Many of these pathways important for ASC to niche crosstalk are pathways also often aberrantly regulated in human cancer.
Some researchers find that the tumor microenvironment plays a key role in the development of drug resistance. And they have demonstrated that stromal cells in the microenvironment are important for modulating a chemotherapy response and are often an indicator of poor prognosis of some kinds of tumors. Some signal way of adult stem cells are related with the drug resistance and the efficacy of chemotherapy.