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Table of Contents Section 1: Bone Marrow Basics 4 The Importance of Normal Bone Marrow 4 The Structure and Function of Normal Bone Marrow 4 Section 2: How Normal Bone Marrow is Used in Research.. 8 Toxicology Studies.. 8 Drug Discovery.... 9 Cell Isolation Studies... 9 Tissue Regeneration Studies.. 10 Genetic Studies..... 10 Biomarker Identification and Validation.. 11 Section 3: How Conversant Bio Can Help.. 12 Conversant Bio Company Information. 13 3
Section 1: Bone Marrow Basics The Importance of Normal Bone Marrow Bone marrow is the birthplace of the human immune system. A wide array of cell progenitors are found within the marrow that help researchers identify the causes of blood and autoimmune diseases. Normal bone marrow plays a vital role in understanding these debilitating diseases and in evaluating treatment options for patients. Furthermore, stem cells obtained from normal bone marrow offer a wealth of possibilities for advancements in regenerative medicine. Consequently, access to high quality, normal bone marrow tissue is essential for medical researcher success. The Structure and Function of Normal Bone Marrow Bone marrow is the soft, sponge-like tissue that fills the hollow center of bones. There are two types of bone marrow: red marrow and yellow marrow. 4
Red Marrow Tissue Type: Consists mainly of hematopoietic tissue, or tissue involved in the formation of red blood cells Prevalence: All bone marrow is red at birth, but about 50% converts to yellow marrow over time. In cases of severe blood loss, yellow marrow can be converted back to red marrow to increase blood cell production. Location: Found primarily in flat bones such as the pelvis, sternum, cranium, ribs, vertebrae, and in the cancellous, sponge-like, material at the rounded ends of long bones such as the femur and humerus Primary Purpose/Function: Produce red blood cells, white blood cells, and platelets Yellow Marrow Tissue Type: Consists mainly of adipocytes (fat cells) Prevalence: None at birth. About 50% of bone marrow differentiates into yellow marrow by adulthood. Location: In the medullary cavity, the hollow interior of the middle portion of long bones Primary Purpose/Function: Store adipocytes whose triglycerides can serve as a source of energy 5
Other Components of Bone Marrow Stroma The stroma is the bone marrow tissue not directly involved in hematopoiesis. It consists mainly of yellow bone marrow and to a lesser extent, stromal cells found in the red bone marrow. The stroma is indirectly involved in hematopoiesis by providing a microenvironment conducive for this process. For example, the stroma produces colony stimulating factors necessary for hematopoiesis. Other cells that constitute the bone marrow stroma include: Fibroblasts Macrophages Adipocytes Osteoblasts Osteoclasts Endothelial Cells Mesenchymal Stem Cells The regenerative properties associated with hematopoietic and mesenchymal stem cells provide extensive potential for regenerative medical treatment. Consequently, understanding the scope of their involvement in hematopoiesis and tissue regeneration has been a key focus for medical researchers. It is estimated that only 1 out of every 100,000 cells in the bone marrow is an uncommitted stem cell, so isolating and studying these cells is especially challenging. 6
Hematopoietic Stem Cells Bone marrow contains hematopoietic stem cells which are progenitors to the three classes of blood cells: leukocytes (white blood cells), erythrocytes (red blood cells), and thrombocytes (platelets). Mesenchymal Stem Cells Bone marrow also contains mesenchymal stem cells (MSCs) which are multipotent stem cells that can differentiate into other cell types including osteoblasts, chondrocytes, myocytes, adipocytes, and beta-pancreatic islets cells. Photo Source: http://www.sci-therapies.info/mesenchymal-stem-cells.jpg 7
Section 2: How Normal Bone Marrow is Used in Research Researchers can use either fresh bone marrow tissue, bone marrow mononuclear cells (BMMCs), or isolated cells in their research. At Conversant Bio, fresh bone marrow is shipped the same day of draw for overnight delivery. BMMCs, consisting mainly of monocytes and lymphocytes, are collected through gradient centrifugation using Ficoll. Conversant Bio can also isolate CD34+ and CD138+ cells from normal marrow. All cells are aliquoted and cryopreserved using techniques that maintain high post-thaw cell viability. BMMC Key Applications: 1. Toxicology Studies Toxicology studies increasingly utilize fresh normal bone marrow samples and mononuclear cells derived from bone marrow to help researchers answer key questions related to new compound toxicity. A key objective during preclinical drug discovery is the assessment of the potentially toxic impact of new compounds on human bone marrow. It is a well-known fact that drug toxicity often manifests in the bone marrow, causing a range of serious side-effects, including neutropenia, mitochondrial toxicity, myelosuppression, immunotoxicity, and other types of bone marrow toxicities. For example, myelotoxicity typically results when the normal proliferation of blood-forming progenitor cells is inhibited. Red and white blood cells, as well as platelets, are significantly reduced or even depleted entirely. Mitochondrial toxicity, which can cause myelosuppression (a decrease in bone marrow activity) and cell death, was the cause for the majority of the 38 drugs withdrawn from the market between 1994 and 2006. 8
Another important reason researchers turn to normal human bone marrow specimens for toxicology studies is to help them predict dosage limits of new drug compounds using a reliable in-vitro model. The maximum tolerated dose (MTD) is frequently a limiting factor in determining an appropriate chemotherapy duration period. Access to human bone marrow sections also provides researchers with information not evident in the examination of peripheral blood alone. For example, exposure to toxic agents can result in bone marrow lesions, inflammatory changes, and bone marrow architecture degeneration. 2. Drug Discovery Early drug discovery efforts rely on human biospecimens to identify and rule out compounds for future in vivo testing. Because bone marrow toxicity is one of the most troublesome and common adverse effects for disease researchers, especially in cancer programs, it is a frequent target for early drug testing. Human BMMCs find wide application in this area. Recently, for example, a research study proposed a model system to identify key protein kinases associated with bone marrow toxicity early on in the drug development process. 3. Cell Isolation Studies Human BMMCs contain approximately one to four percent of CD34+ progenitor cells; these are a highly purified population of progenitor cells. CD34+ progenitors are frequently isolated from normal BMMCs and used for a range of in vitro tests, such as molecular isolation of proteins and nucleic acids, cytokine studies, cell activation, and cell proliferation and translational research. Isolated CD34+ cells have also been used in clinical settings as a treatment for various diseases including liver cirrhosis and peripheral vascular disease. 9
4. Tissue Regeneration Studies Irritable bowel disease (IBD) is a vexing disorder thought to be caused by an immune response to the body s own intestinal tissue. Current therapies are able to treat the symptoms of this debilitating disease, but no cure is presently available. Recently, researchers have located a particular type of adult stem cell found in normal bone marrow that can migrate to the intestine and create healthy intestinal cells. It is theorized that these may potentially restore healthy tissue in patients suffering with IBD. Normal bone marrow has also shown promise as a potential treatment for bladder disease. Serious bladder disease sometimes requires the placement of a patch from the patient s own bowel over part of the diseased bladder. This approach has challenges, however, since the introduced tissue tends to cause long-term complications, such as bladder cancer. Novel research involves harvesting a patient s healthy, normal bone marrow tissue and using it to recreate the bladder s smooth muscle, vasculature, and nerve tissues. 5. Genetic Studies Human mesenchymal stem cells (hmscs) derived from normal human bone marrow have many therapeutic applications. In one study, researchers endeavored to more fully understand the genetic pathways that operate during an hmsc invasion and explore how to use this information to develop more highly targeted therapies. The authors concluded that a variety of genes involved in immune maintenance, developmental processes, and regulation of so-called stemness were increased in invasive hmscs. 10
Another clinical study is currently investigating leukocytosis, or elevated white blood cell levels, by collecting normal bone marrow and blood samples to compare to samples from patients with elevated white blood cell counts. The study administrators collect blood and bone marrow samples from normal volunteers who meet standard blood donor criteria. According to the published protocol, some of the collected samples will be used for genetic testing or future research on diseases caused by this condition. 6. Biomarker Identification and Validation A biomarker is a biological characteristic that can be measured to indicate a biological state or condition. Biomarkers are used in clinical settings to evaluate normal biological processes, pathogenic states, and pharmaceutical treatment responses. Proteins derived from BMMCs have been shown to act as valid biomarkers. For example, one study found that the BTG1 protein was upregulated in patients in remission from acute myeloid leukemia (AML) as well as in normal bone marrow samples. AML patients who received treatment but did not achieve remission exhibited lower BTG1 levels, indicating that this BMMC derived protein could be used as a potential treatment-related biomarker for monitoring the remission status of AML patients. 11
Section 3: How Conversant Bio Can Help Supply fresh marrow, BMMCs, and isolated CD34+ and CD138+ from normal bone marrow tissue. Deliver fresh normal bone marrow within 24 hours of collection Provide more cells per fresh marrow sample when compared to leading competitors Access a wide variety of donors from our cryopreserved inventory. Our hyper-annotated samples include information about patient demographics, medical history, and physical condition. Match normal donors by age to compare to diseased samples. Our age matching capabilities ensure that you receive samples relevant to your target population. Ensure a short lead time between your order and deliveries. Conversant Bio s lead time is less than 1 week. 12
Company Information Take Your Research Further. Faster. Conversant Healthcare Systems, Inc. (Conversant Bio) 601 Genome Way, Suite 1200 Huntsville, AL 35806 (866) 838-2798 phone (256) 705-4103 fax www.conversantbio.com To find out how we can help with your research needs, email us at sales@conversantbio.com 13