WFIRM Scientists Create Primitive Circulatory System with Chip Platform Model

November, 2019 – Scientists at the Wake Forest Institute for Regenerative Medicine (WFIRM) have developed a novel on-a-chip system that recreates the biology of human bone marrow, creating a primitive circulatory system. The bone marrow-on-a-chip platform model allows researchers to study normal and malignant hemopoietic cell-niche interactions. Hematopoietic niches are specialized sites within the bone marrow that promote the maintenance of blood stem/progenitor cells and regulate production of mature cells. These niches can be altered in disease, and after bone marrow transplantation conditioning regimens.
The hematopoietic system supplies the human body with 100 billion mature blood cells every day that carry out functions such as oxygen transport, immunity, and tissue remodeling. Hematopoietic stem cells are responsible for replenishing our pool of blood cells throughout life. In recent years a small number of studies performed investigating alterations of these sites have been performed, but in animal models, which may not correlate completely to their human counterparts. The WFIRM research team is using this system to imitate and study preferential human blood stem cell/niche cell interactions with the ultimate goal of using this knowledge to develop more effective treatments for hematological malignancies and enhance engraftment following bone marrow transplant.
“In our study, we report the feasibility of producing ‘in vitro’ avatars that recreate the hematopoietic microenvironment using microfluidic on-a-chip technology,” said one of the lead researchers and co-author Graca Almeida-Porada, MD, PhD. “This technology will enable us to better understand the normal function of the human bone marrow, study interactions of human blood stem cells with specific healthy and altered bone marrow niches, and investigate therapeutic options for patients.”
For this study, published in the journal Nano-Micro Small, the researchers disentangled the bone marrow microenvironment by breaking it down into 3D tissue constructs – also known as organoids – representing the four major hematopoietic niches that exist within it. The constructs are housed within a single, closed, recirculating microfluidic device that has microchannels that allow for the continuous flow of human hematopoietic stem/progenitor cells through each of the specific niches, “reproducing, in effect, a primitive circulatory system,” Almeida-Porada said.
Within the microfluidic devices, leukemia, lymphoma or normal blood cells, had an equal chance to interact with the different bone marrow niches, yet the researchers found that each cell population exhibited a marked predilection for interacting and subsequently making residence within particular niches. Importantly, these preferences differed between normal/healthy and malignant human HSPC, and also differed depending upon the type of malignancy, such that HSPC lines from leukemia and lymphoma patients exhibited distinct patterns of niche-on-a-chip homing and lodging/retention.

“Specifically, defining the differences within normal versus malignant niches that alter the interactions with human blood stem cells could lead to novel therapies that could ultimately pave the way for safer and more effective personalized medicine approaches in the clinic,” said Anthony Atala, M.D., director of WFIRM.
Co-authors include Julio Aleman, Sunil K. George, Samuel Herberg, Mahesh Devarasetty, Christopher D. Porada and Aleksander Skardal.
The research is supported with funding from the Wake Forest Baptist Medical Center Clinical and Translational Science Institute Open Pilot Program via NIH CTSA UL1 Tr001420; NIH R21HL117704; and NHLBI R01HL135853 and R01HL130856. The authors declare no conflicts of interest.