The characterization and isolation of various stem cell populations, from embryonic through tissue-derived stem cells, have led a rapid growth in the field of stem cell research. These research efforts have often been interrelated as to the markers that identify a select cell population are frequently analyzed to determine their expression in cells of distinct organs/tissues. In this review, we will expand the current state of research involving select tissue-derived stem cell populations including the liver, central nervous system, and cardiac tissues as examples of the success and challenges in this field of research. Lastly, the challenges of clinical therapies will be discussed as it applies to these unique cell populations.
Stem cells are broadly defined as cells capable of going through numerous cycles of cell division, maintaining an undifferentiated state and having the capacity to differentiate into specialized cell types. They will often go through asymmetric division where the stem cell creates a copy of itself and a daughter cell that is capable of differentiation [
Several challenges persist when investigating individual stem cell populations [
Identifying and isolating somatic stem cells from mature organs is a greater challenge. Pluripotent cells are thought to exist in most adult tissues, but their low frequency and lack of identified unique cell surface markers make it difficult to isolate these cells. Maintaining these stem cells in an undifferentiated state or even directing their differentiation requires understanding the signaling pathways that naturally occur in the cells’ extracellular environment (e.g., the “stem cell niche’’). The local milieu provides critical signals for most stem cell populations to continue self-renewal [
The human pancreas is a glandular organ that serves both endocrine and exocrine functions. The exocrine pancreas is comprised of acinar, centroacinar, and duct cells. These cells manufacture and secrete enzymes and alkaline fluids into the intestinal tract to facilitate digestion. The endocrine pancreas consists of the Islets of Langerhans which are mixed cell clusters that produce hormones for excretion into the blood stream. These cell-type-specific hormones include insulin and glucagon which are essential in glucose regulation. Other hormones produced in the Islets of Langerhans include somatostatin which is important in digestive regulation.
The pancreas has been implicated in many disease states [
Embryologic development of the pancreas has been closely studied and known mediators and transcription factors have been identified in pancreatic development. Activin- and (fibroblast growth factor-2) FGF-2 mediated repression of sonic hedgehog expression have been implicated in pre-pancreatic development from dorsal endoderm [
Human embryonic stem cells have been successfully cultured to create pancreatic islet cells that produce insulin and C-peptide in response to glucose stimulation. Jiang et al. describe a 36-day protocol that involves mixing human embryonic stem cells (HESCs) in vitro with Pdx1, Ptf1a/p48, Activin, and FGF in a sequential fashion to drive differentiation into functional pancreatic cells [
Identification and isolation of a defined pancreatic stem cell capable of giving rise to
Some of the most advanced clinical studies have come from the use of bone marrow-derived stem cells. Karnieli et al. demonstrated that bone marrow stem cells induced with Pdx1 and other factors can functionally resemble pancreatic cells [
Overall, the clinical need for appropriate therapies for the treatment of type 1 diabetes is clear. The number of patients that undergo pancreas or islet cell transplant remains limited relative to the number of patients afflicted with this disease. The breadth of efforts in stem cell research from embryonic stem cells through adult pluripotent cells has been somewhat successful in animal models. Translational efforts in clinical trials will be the obvious critical step in the domain of diabetes therapy.
The human heart is a muscular organ that is responsible for pumping oxygenated blood from the lungs to peripheral tissues. The cardiac tissue is comprised of three layers. The innermost layer is the endocardium which lines the inner chambers of the heart. Surrounding this is the myocardium which consists of cardiac myocytes (i.e., involuntary striated muscle cells). These cells contract in response to electrical stimuli. The fibrous epicardium functions as a scaffold to provide shape and form to the heart. Blood supply arrives to the cardiac tissue through the coronary vessels.
Heart disease is the number one cause of mortality in the United States. A myocardial infarction occurs secondary to a blockage in the coronary vessels supplying the cardiac myocytes. Myocytes die in response to the ischemic event thereby forming a scar in the tissue. Surrounding the infracted area is a region of stunned or “hibernating’’ myocardium. The likelihood of acutely dying from a myocardial infarct has decreased 30% over the past 20 years, because of improvements in management of heart disease. However, the number of people living with compromised heart function has nearly doubled over the same period [
Cardiac-myocyte-like cells have been induced from embryonic stem cells by coculture with endodermal feeder layers and/or growth factors. These induced cell populations form contractile tissue that expresses troponin and other markers demonstrated in mature cardiac myocytes [
Studies of heart transplant recipients demonstrate that host cells from hematopoietic origins can repopulate the new myocardium [
Large-scale studies to assess the effectiveness of bone marrow stem cell implantation after myocardial infarction include the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) and Bone MarrOw Transfer to Enhance ST-elevation infarct regeneration (BOOST) trials. In the REPAIR-AMI trial, patients who experienced a myocardial infarct were randomized to receive either intracoronary infusion of bone marrow cells or placebo after traditional revascularization procedures (e.g., stenting). The primary measured outcomes were: left ventricular ejection fraction (LVEF), recurrent MI, additional revascularization procedures, heart failure, and death. LVEF improved over time in both the BMC recipient group as well as the placebo group but the improvement was significantly greater at four months in the bone marrow transplant group (
The BOOST trial, like the REPAIR-AMI trial, included patients with an acute ST elevation myocardial infarction who underwent percutaneous coronary intervention (PCI). Patients were prospectively randomized to receive optimal medical therapy or medical therapy plus bone marrow cell transplant [
Ongoing trials have investigated the delivery and timing of stem cell infusions in relation to the cardiac event. While the optimal time for transplantation has not been delineated in a randomized trial current data suggests that the most effective time of delivery may be between 5–8 days after the ischemic event [
Studies involving embryonic-derived cardiac myocytes have shown some functional success, but thus far have been limited to animal models [
The human liver is the body’s chief metabolic organ. It is comprised of several cell types including hepatocytes, cholangiocytes, kupffer cells, stellate cells and endothelial cells. Among its many functions are the production of proteins, the regulation of blood glucose levels, and enzymatic degradation of toxins within the body.
Due to the liver’s essential regulatory and synthetic functions, hepatic failure is a life threatening condition. Although hepatic regeneration can occur via terminally differentiated hepatocytes, this regenerative capacity remains insufficient in the majority of disease states and a patient may subsequently require liver transplantation. Due to the shortage of available organs and the need for lifelong immunosuppression, ongoing research is focused on strategies to repopulate the liver with functioning hepatocytes through cell transplantation.
Embryonic stem cells serve as a potential source for cell transplantation to reconstitute the diseased liver [
Efforts to identify a somatic-derived pluripotent cell within the liver have led to the discovery of several multipotent cell types. Examples of multipotent cells include the hepatoblast and oval cell. In the fetal liver, hepatoblasts serve as precursors for hepatocytes as well as cholangiocytes. These cells are characterized by specific cell surface markers including alpha-fetoprotein (AFP), EpCAM, and cytokeratins 17 and 19 [
In the adult liver, a bipotent progenitor cell capable of forming both liver and biliary epithelium has been identified. These cells, termed oval cells, reside in the terminal bile ducts of the adult liver, and maintain a high nuclear/cytoplasmic ratio [
The adult derived hepatic progenitor cell is another cell type found in the liver and localized to the “Canals of Herring.’’ They appear distinct from the hepatoblast or the oval cell as they are encountered without a preceding injury to the tissue. Further investigations will need to be performed to understand the overlap amongst the various hepatic populations [
Hepatocytes obtained from adult livers have been used in clinical trials to treat liver disease ranging from fulminant liver failure to inherited metabolic disorders [
Initial studies using embryonic stem cell-derived hepatocytes as well as induced pluripotent cells are underway in animal models. Kumashiro et al. demonstrated improved liver function in mice with chemically induced liver injury after transplantation with embryonic stem cell-derived hepatocytes [
The nervous system, a network of neurons and supporting cells that interpret and respond to stimuli, is divided into two compartments. The central nervous system (CNS) is comprised of the brain and spinal cord. Oligodendrocytes are cells that create the myelin sheath that surround the neurons of the CNS. Myelination protects the neurons and aids in the speed of signal transmission. The peripheral nervous system (PNS) supplies sensory and motor information to and from the extremities. Schwann cells myelinate the nerves of the peripheral nervous system.
While peripheral nerves have some regenerative capacity, damage to the central nervous system usually results in permanent disability. Therefore, degenerative conditions such as Parkinson’s disease and multiple sclerosis are devastating diagnoses. Similarly, traumatic spinal cord injury usually results in irreversible paralysis. Treatment for these conditions has traditionally been limited to supportive therapy. Recent investigations have demonstrated a population of pluripotent cells within the CNS that is responsible for repair and regeneration. Recent efforts have been directed towards harnessing the potential of these cells for therapeutic use.
Embryonic stem cells can be induced to form neurons and other functional neural tissue. Ben-Hur et al. demonstrated that functional neuronal cells could be derived from primate embryonic stem cells using a stromal feeder coculture system for neural induction with sequential exposure to inductive signals, such as sonic hedgehog (SHH) and FGF-8. This approach controls dopaminergic specification during embryogenesis. After transplantation into immunosuppressed rats these cells maintain functional stability for 12 weeks [
During development, the brain arises from a layer of neuroepithelial stem cells that surrounds the lumen of the early neural tube. Recent investigation has demonstrated that multipotent neural stem cells continue to line the cerebral ventricles of the forebrain in the adult brain. These cells have been isolated and grown in culture. When transplanted into neural tissue, the multipotent neural stem cells differentiate into neurons and supportive neural tissue including oligodendrocytes and glial cells [
Clinical applications of embryonic and somatic derived neural stem cells are under investigation for treatment of diseases that were once thought to be irreversible (e.g., Parkinson’s disease, multiple sclerosis and traumatic spinal cord injury). The following is a contemporary description of progress in this field.
Parkinson’s disease results from destruction of nigrostriatal dopamine containing neurons and physiologically manifests as rigidity, bradykinesia, tremor, and postural instability. Medical therapies to increase dopaminergic function have limited efficacy due to side effects and durability of the treatment. Promising results using stem cell based therapies have been reported by a number of groups using preclinical models, but clinical safety and the long term outcomes have not been demonstrated [
Current therapeutic efforts for spinal cord injuries are directed at limiting progression of disease rather than repairing the existing damage. Isolation of neural progenitor cells from adult or embryonic tissue may represent a novel therapeutic approach [
A limitation of stem cell transplantation of neural tissue involves the low level of integration and stability of the derived cells. Therefore, transplantation of a viable number of these cells leading to durable functioning grafts will need to be addressed for the initiation of clinical trials.
In all of the described research areas, one of the crucial elements involves understanding the processes that enable stem cells to regenerate or differentiate. In adult tissue there are relatively few stem cells within a given organ. Harnessing the ability to expand these cells and maintain their undifferentiated state is important before large scale therapeutics can be realized. Purifying the cells and preventing teratoma formation is paramount to ensure the safety of stem cell therapies. Initial work with the forkhead 0 (fox0) family of transcription factors suggests that these factors may be involved in cell cycle arrest, differentiation, and apoptosis [
The field of stem cell research continues to expand with characterization and isolation of various stem cell populations from the embryonic stem cell to tissue-derived cell populations. The clinical applications of embryonic stem cells are limited by ethical concerns and the potential of teratoma formation. Pluripotent cells which persist in mature organs are also targeted for cellular transplantation or organ regeneration. Recent gains in the understanding of the stem cell niche and the signaling pathways which drive stem cell differentiation have enabled investigators to induce readily available cells such as adipocyte and hematopoietic derived cells into other tissue types.
In this review we discussed four organ systems, the pancreas, liver, heart, and neural systems. These were selected due to the magnitude of their disease burden on society. However, it should be recognized that stem cells are also under clinical investigation in the fields of plastic and reconstructive surgery [