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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

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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.

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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

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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.

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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

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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 pre-

clinical 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.

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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.

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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.

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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.

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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.

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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