Future medicine: from molecular pathways to the collective intelligence of the body.

The remarkable anatomical homeostasis exhibited by complex living organisms suggests that they are inherently reprogrammable information-processing systems that offer numerous interfaces to their physiological and anatomical problem-solving capacities. We briefly review data suggesting that the multiscale competency of living forms affords a new path for biomedicine that exploits the innate collective intelligence of tissues and organs. The concept of tissue-level allostatic goal-directedness is already bearing fruit in clinical practice.

Fat-associated lymphoid clusters as expandable niches for ectopic liver development.

Background And Aims: Hepatocyte transplantation holds great promise as an alternative approach to whole-organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process.

Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure.

The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced with a lentiviral vector carrying the pig gene and transplanted into mesenteric lymph nodes.

Development of Ectopic Livers by Hepatocyte Transplantation Into Swine Lymph Nodes.

Orthotopic liver transplantation continues to be the only effective therapy for patients with end-stage liver disease. Unfortunately, many of these patients are not considered transplant candidates, lacking effective therapeutic options that would address both the irreversible progression of their hepatic failure and the control of their portal hypertension. In this prospective study, a swine model was exploited to induce subacute liver failure.

Host Lymphotoxin-β Receptor Signaling Is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites.

The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-β receptor (LTβR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTβR antagonist treatment or in the omenta of Ltbr knockout (Ltbr) mice, the host LTβR signals were found to be crucial for obtaining a well-vascularized kidney graft.

Kidney-in-a-lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates.

Stem cell-derived organoids are emerging as sophisticated models for studying development and disease and as potential sources for developing organ substitutes. Unfortunately, although organoids containing renal structures have been generated from mouse and human pluripotent stem cells, there are still critical unanswered questions that are difficult to attain via in vitro systems, including whether these nonvascularized organoids have a stable and physiologically relevant phenotype or whether a suitable transplantation site for long-term in vivo studies can be identified. Even orthotopic engraftment of organoid cultures in the adult does not provide an environment conducive to vascularization and functional differentiation.

Establishment and Characterization of 5-Fluorouracil-Resistant Human Colorectal Cancer Stem-Like Cells: Tumor Dynamics under Selection Pressure.

5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms of drug resistance, CRC stem-like cells were subjected to long-term 5-FU selection using either intermittent treatment regimen with the IC50 drug dose or continuous treatment regimen with escalating drug doses.

Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney.

Background & Aims: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers because of its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through complex intercellular signaling. However, the mechanism of liver organogenesis, especially the role of adult hepatocytes at ectopic sites, remains unknown.

Towards Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis.

In recent years, functional three-dimensional (3D) tissue generation in vitro has been significantly advanced by tissue-engineering methods, achieving better reproduction of complex native organs compared to conventional culture systems. This review will discuss traditional 3D cell culture techniques as well as newly developed technology platforms. These recent techniques provide new possibilities in the creation of human body parts and provide more accurate predictions of tissue response to drug and chemical challenges.

Transplantation of hepatocytes from genetically engineered pigs into baboons.

Background: Some patients with acute or acute-on-chronic hepatic failure die before a suitable human liver allograft becomes available. Encouraging results have been achieved in such patients by the transplantation of human hepatocyte progenitor cells from fetal liver tissue. The aim of the study was to explore survival of hepatocytes from genetically engineered pigs after direct injection into the spleen and other selected sites in immunosuppressed baboons to monitor the immune response and the metabolic function and survival of the transplanted hepatocytes.

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas.

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens.

Regenerating a kidney in a lymph node.

The ultimate treatment for end-stage renal disease (ESRD) is orthotopic transplantation. However, the demand for kidney transplantation far exceeds the number of available donor organs. While more than 100,000 Americans need a kidney, only 17,000 people receive a kidney transplant each year (National Kidney Foundation's estimations).

Therapeutic potential of mTOR inhibitors for targeting cancer stem cells.

The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many cancer types. As the intricate network of regulatory mechanisms controlling mTOR activity is uncovered, more refined drugs are designed and tested in clinical trials. While first generation mTOR inhibitors have failed to show clinical efficacy due partly to the feedback relief of oncogenetic circuits, newly developed inhibitors show greater promise as anti-cancer agents.

Tissue-Specific Effects of Esophageal Extracellular Matrix.

Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate repair or remodeling of numerous tissues, including the esophagus. The theoretically ideal scaffold for tissue repair is the ECM derived from the particular tissue to be treated, that is, site-specific or homologous ECM. The preference or potential advantage for the use of site-specific ECM remains unknown in the esophageal location.

Pluripotent Stem Cells to Rebuild a Kidney: The Lymph Node as a Possible Developmental Niche.

Kidney disease poses a global challenge. Stem cell therapy may offer an alternative therapeutic approach to kidney transplantation, which is often hampered by the limited supply of donor organs. While specific surface antigen markers have yet to be identified for the analysis and purification of kidney stem/progenitor cells for research or clinical use, the reprogramming of somatic cells to pluripotent cells and their differentiation into the various kidney lineages might represent a valuable strategy to create a renewable cell source for regenerative purposes.

Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice.

Identification of a candidate stem cell in human gallbladder.

There are currently no reports of identification of stem cells in human gallbladder. The differences between human gallbladder and intrahepatic bile duct (IHBD) cells have also not been explored. The goals of this study were to evaluate if human fetal gallbladder contains a candidate stem cell population and if fetal gallbladder cells are distinct from fetal IHBD cells.

Distinct human stem cell populations in small and large intestine.

The intestine is composed of an epithelial layer containing rapidly proliferating cells that mature into two regions, the small and the large intestine. Although previous studies have identified stem cells as the cell-of-origin for intestinal epithelial cells, no studies have directly compared stem cells derived from these anatomically distinct regions. Here, we examine intrinsic differences between primary epithelial cells isolated from human fetal small and large intestine, after in vitro expansion, using the Wnt agonist R-spondin 2.

The lymph node as a new site for kidney organogenesis.

The shortage of organs for kidney transplantation has created the need to develop new strategies to restore renal structure and function. Given our recent finding that the lymph node (LN) can serve as an in vivo factory to generate or sustain complex structures like liver, pancreas, and thymus, we investigated whether it could also support kidney organogenesis from mouse renal embryonic tissue (metanephroi). Here we provide the first evidence that metanephroi acquired a mature phenotype upon injection into LN, and host cells likely contributed to this process.

Maturation of embryonic tissues in a lymph node: a new approach for bioengineering complex organs.

Given our recent finding that the lymph node (LN) can serve as an in vivo factory to generate complex structures like liver, pancreas, and thymus, we investigated whether LN could also support early development and maturation from several mid-embryonic (E14.5/15.5) mouse tissues including brain, thymus, lung, stomach, and intestine.

Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population.

Because the esophageal epithelium lacks a defined stem cell niche, it is unclear whether all basal epithelial cells in the adult esophagus are functionally equivalent. In this study, we showed that basal cells in the mouse esophagus contained a heterogeneous population of epithelial cells, similar to other rapidly cycling tissues such as the intestine or skin. Using a combination of cell-surface markers, we separated primary esophageal tissue into distinct cell populations that harbored differences in stem cell potential.

Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice.

The PTP4A3 gene is highly expressed in human colon cancer and often associates with enhanced metastatic potential. Genetic disruption of the mouse Ptp4a3 gene reduces the frequency of colon tumor formation in mice treated in a colitis-associated cancer model. In the current study, we have examined the role of Ptp4a3 in the tumor-initiating cell population of mouse colon tumors using an in vitro culture system.

Ectopic transplantation sites for cell-based therapy.

Purpose Of Review: This review outlines the concept of cell-based therapy to restore tissue function, and addresses four key points to consider in cell transplantation: source, surveillance, safety, and site. Whereas each point is essential, additional attention should be given to transplantation sites if cell therapy is going to be successful in the clinic. Various ectopic locations are discussed, and the strengths and weaknesses of each are compared as suitable candidates for cell therapy.

mTOR pathway in colorectal cancer: an update.

The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic effectiveness remains unclear.