Scientists explore making of RBCs from in-vitro stem cells

The main challenges faced are selecting an appropriate stem cell source with long-term repopulating progenitors and differentiating them to erythroid lineage to yield functional RBCs.

Umbilical cord blood cells, from cord blood, is a potent candidate. They are easily accessible and banked, with non-invasive collection procedure and a low probability of host rejection and viral contamination. Scientists have successfully cultured them using different methods. However, questions exist regarding the cost-effectiveness. Also, the RBCs contain predominantly fetal Hemoglobin (Hb). An optimized culture system with bone marrow stem cells yielded RBCs with lesser fetal Hb content.

Peripheral blood is more readily available. However, it contains a smaller percentage of Hematopoietic Stem Cells (HSCs). This source also faces the drawbacks of a higher chance of host-donor rejection and expensive recombinant differentiation factors.

Induced pluripotent stem cells (iPSC) are induced from mouse fibroblast cells. They heavily resemble embryonic stem cells (ESC), while avoiding the ethical problems regarding the origin of the latter. The procedure of RBC generation from iPSC appears promising, and with a better yield. However, the cost factor is high, and the safety of iPSC derived RBCs require critical evaluation. ESCs themselves are another viable option, with the process resembling fetal erythropoiesis the most. Ethical problems are the major concern for this option.

There are various ways to culture and expand the HSCs. The 2D static system cocultures HSCs on an adherent layer of stromal cells. They are severely limited, however, as they poorly mimic the physiological environment of the bone marrow. The fixed nature of the cells increase chances of clumping and hinder uniform diffusion of nutrients. The culture also requires repeated handling and is impossible to monitor. The 3D scaffolding system uses materials such as cellulose, gelatin, ceramic foam, PET provides architecture similar to the native bone marrow. Bioreactors are yet another option which mimics the natural non-adherent nature of HSCs. Bioreactors with matrices that are fed through hollow fiber technology simulate the hypoxic conditions of the bone marrow. These conditions greatly increased yield, with an enucleation frequency of 90%. The challenge lies in expansion from small-scale to large-scale application.

A large-scale adoption of in-vitro manufactured RBCs can tremendously improve transfusion medicine. If the challenging aspects of expanding and differentiating the HSCs while maintaining control over the several critical parameters are achieved, it would especially help patients in need of a frequent transfusion. It would also eliminate the constraints of blood group matching and screening for diseases and disorders.