Idiopathic aplastic anemia (AA) is a rare disease characterized by a bone marrow (BM) hypocellularity, in which hematopoietic cells are replaced by fat cells, resulting in severe reductions in the numbers of hematopoietic stem/progenitor cells (HSPC). Despite the first line treatment option for severe AA would be allogeneic hematopoietic cell transplant (HCT), this procedure is not always feasible or well-succeeded, due to several constraints (e.g. unavailability of a suitable donor; risk of toxicity and engraftment failure, especially in older patients; rejection, which is estimated to occur in 5% to 15% of patients with severe AA undergoing BM transplantation).

The BM microenvironment, which comprises mesenchymal stromal cells (MSC), among other cellular and non-cellular elements as the extracellular matrix (ECM), has been related to AA pathophysiology. BM MSC provide cellular and structural elements required to support hematopoiesis and have been shown to support hematopoiesis by paracrine mechanisms, such as secretion of bioactive molecules that support proliferation of HSPC. Concerning the MSC role in AA, published data are controversial, probably due to the heterogeneity between patients and to technical differences between research protocols.

The central research hypothesis to be tested in BIOaptAA is the modulation of the altered BM niche in an AA context, namely related with MSC-derived elements (cellular and non-cellular), which can induce intrinsic defects in HSPC (e.g. impaired proliferative and differentiative capacity) and contribute to the development of BM failure, towards the development of personalized medicine strategies for AA. To this end, we will develop a microfluidic cell culture device as a bioengineered BM proxy, featuring the co-culture of HSPC and MSC, able to (i) recapitulate specific pathological features of AA and enable disease modelling; and (ii) foster identification of new drug targets and combinations, as well as predicting drug response towards the development of more efficacious therapeutic regimens for AA. A deeper characterization of BM MSC and HSPC from both AA (newly diagnosed AA patients without previous treatment) and healthy donors will be performed and it is expected to generate important biological insights concerning the BM microenvironment role on AA pathophysiology and HSPC dysfunction.

The ultimate goal would be to develop new therapeutic strategies for AA, in order to circumvent present treatment limitations that imply poor outcomes and significant morbidity and mortality rates, especially in adult and elderly patients.

BIOaptAA is truly collaborative, by exploiting complementary expertise in Stem Cell Engineering, Cell Biology, Microfluidics and Hematology. IST-ID/iBB team has been establishing an international research track record across Stem Cell Engineering and Regenerative Medicine, with important contributions in the field of the ex-vivo expansion of human HSPC and MSC in scalable culture systems and towards a better understanding of the mechanisms underlying the hematopoietic supportive capacity of human MSC. The project consortium includes INESC MN dedicated to leading edge research and development in strategic technological areas of micro and nanotechnologies with important contributions on the development of microfluidic-based systems for several biotechnology applications. IST-ID/iBB and INESC MN integrate the Associate Laboratory i4HB- Institute for Health and Bioeconomy funded by FCT and BIOaptAA is expected to have a major impact in its thematic lines 1 – Platforms for Drug Discovery and Development & 2 – Advanced Diagnostics and Therapies.