Researchers discover mechanism that helps control blood cell production in bone marrow

Scientists from Torrey Pines Institute for Molecular Studies and their collaborators have discovered that a long-chain sugar molecule contributes to blood cell production in the bone marrow. In healthy people, the bone marrow produces about 500 billion red and white blood cells every day. When the bone marrow is damaged by radiation, chemotherapeutic drugs, or disease, the decrease in blood cell production can compromise the immune system and lead to lethal infections.

Millions of patients around the world suffer from acute and chronic illnesses caused by blood cell deficiencies. The study, published in the July 20th issue of the Journal of Biological Chemistry, could pave the way for new therapeutics that stimulate production of blood cells and improve the way that bone marrow stem cells are used to treat diseases.

In the study, the international team of scientists, led by Dr. Sophia Khaldoyanidi, studied a long-chain sugar called hyaluronan, which is synthesized by many cells in the body. The team showed that mice that could not synthesize hyaluronan had defective bone marrow that was unable to retain hematopoietic stem and progenitor cells—cells that give rise to the full range of mature blood cells—and caused them to move to other organs.

Further studies showed that tight control of hyaluronan levels in the bone marrow was critical for the microenvironment to generate signals supporting stem cell function. “Our findings suggest that hyaluronan is a biologically active component of the hematopoietic microenvironment and is involved in regulating hematopoietic homeostasis,” said Dr. Khaldoyanidi. Because too much or too little hyaluronan in the bone marrow caused abnormalities in hematopoiesis, the scientists believe that biologically active forms of hyaluronan or hyaluronan synthesis-blocking drugs may have potential use in the clinic to correct misbalanced hyaluronan levels and help support blood cell production.

Bone marrow cultures show hematopoietic cells (visible as small bright round cells) and components of the microenvironment (visible as a lower layer of dark and adherent cells). Cultures treated with the chemical 4-methylumbelliferone (4MU), an inhibitor of hyaluronan synthesis, (right) show a dramatic reduction in numbers of hematopoietic cells compared with untreated cultures (left). Bone marrow cultures show hematopoietic cells (visible as small bright round cells) and components of the microenvironment (visible as a lower layer of dark and adherent cells). Cultures treated with the chemical 4-methylumbelliferone (4MU), an inhibitor of hyaluronan synthesis, (right) show a dramatic reduction in numbers of hematopoietic cells compared with untreated cultures (left).

“Dr. Khaldoyanidi's elegant studies provide seminal evidence of the key role of hyaluronan in the hematopoietic microenvironment. The work has profound implications for clinical practice, as it suggests that maintenance of marrow hyaluronan levels could improve blood cell development,” said Dr. Robert Sackstein, a leading bone marrow transplant physician-scientist and Professor at the Harvard Medical School.

The study was evaluated by the Faculty of 1000, in which the world's leading scientists and clinicians identify and evaluate the most important articles in biology and medical research. “The fact that the Faculty of 1000 is now paying attention to hyaluronan research is great. As most of us in the field know, it has been difficult at times to get the broader research community to pay attention to hyaluronan matrices and their roles in normal and pathological processes,” said Vincent Hascall, PhD, Professor and Head, Section of Connective Tissue Biology, Cleveland Clinic Lerner Research Institute.

Researchers involved in this study were: Valentina Goncharova, Ingrid Schraufstatter, Tatiana Povaliy, Valentina Wacker, Audrey de Ridder, and Sophia Khaldoyanidi from Torrey Pines Institute for Molecular Studies, San Diego, CA; Naira Serobyan from La Jolla Institute for Molecular Medicine, San Diego, CA; Shinji Iizuka and Yu Yamaguchi from Sanford-Burnham Medical Research Institute, La Jolla, CA; Irina A. Orlovskaja from Institute of Clinical Immunology, Novosibirsk, Russia; Naoki Itano from Kyoto Sangyo University, Kyoto, Japan; and Koji Kimata from Aichi Medical University, Nagakute, Japan.

Original paper: Hyaluronan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis. Goncharova V, Serobyan N, Iizuka S, Schraufstatter I, de Ridder A, Povaliy T, Wacker V, Itano N, Kimata K, Orlovskaja IA, Yamaguchi Y, Khaldoyanidi S. J Biol Chem. 287, 25419–25433. PMID: 22654110

The study was supported by National Institutes of Health Grants R41CA126004, R43AI082759, R21NS062428, and University of California TRDRP Grant 16RT-0134.