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Exploring Advanced Culture Substrates to Enhance Stem Cell Transplants

Review of  “Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel” from Nature Medicine by Stuart P. Atkinson

Research efforts from the laboratories of Shaoyi Jiang and Colleen Delaney (University of Washington, Seattle, WA, USA) have established that cord blood transplant recipients exhibited a survival advantage compared with matched and mismatched unrelated donor transplant recipients in leukemia patients undergoing myeloablative therapy [1]. As low stem cell doses present in cord blood transplants can delay hematopoietic recovery [2], many have sought to develop novel approaches to increase the absolute number of hematopoietic stem and progenitor cells (HSPCs) in vitro to improve outcomes. With this in mind, the Jiang and Delaney laboratories developed an ex vivo CD34+ HSPC expansion protocol employing an engineered Notch ligand that inhibited differentiation, increased absolute cord blood HSPC numbers, and thereby accelerated hematopoietic recovery following myeloablation in a clinical trial setting  [3, 4]. 

In the hope of further improving this strategy, the team recently explored the application of culture substrates that mimic the in vivo three dimensional (3D) stem cell niche, an environment dominated by hydrophilic and zwitterionic cell-membrane lipids [5], given that recent reports described reduced HSPC differentiation on highly hydrophilic 3D substrates [6]. Now, Bai et al. report that the encapsulation and ex vivo culture and amplification of HSPCs inside super-hydrophilic, non-specific interaction-resistant, and degradable zwitterionic poly(carboxybetaine)-based reversibly-crosslinked hydrogels have the potential to enhance clinical outcomes of HSPC-based therapies [7]. 

In brief, the implementation of a 3D zwitterionic hydrogel culture substrate permitted the preservation and subsequent expansion of primitive CD34+ cord blood and bone-marrow-derived HSPCs, with said cells exhibiting much- long-term repopulating ability both improved in vitro and in vivo. Furthermore, HSPCs expanded under these conditions supported hematopoietic reconstitution in immunocompromised mice for at least 24 weeks. But what mechanism controls such an improvement? The authors hypothesize that the 3D zwitterionic hydrogels may have prevented HPSC differentiation and promoted HPSC self-renewal by inhibiting the excessive production of reactive oxygen species through the suppression of oxygen-dependent metabolism.

While the authors highlight HSPC expansion using 3D zwitterionic hydrogels as a means to facilitate the clinical application of hematopoietic stem- cell therapies, they also underline the need for further investigation. To this end, the team hope to comprehensively study the cells expanded on the zwitterionic hydrogels with regards to their capacity to generate multiple hematopoietic lineages and a functional human immune system upon transplantation into different animal models, while also exploring the expansion of additional cell lines, including embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells.

For more on how advanced culture substrates can boost stem cell transplants, stay tuned to the Stem Cells Portal!


  1. Milano F, Gooley T, Wood B, et al., Cord-Blood Transplantation in Patients with Minimal Residual Disease. New England Journal of Medicine 2016;375:944-953.
  2. Ballen KK, Gluckman E, and Broxmeyer HE, Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013;122:491-498.
  3. Delaney C, Heimfeld S, Brashem-Stein C, et al., Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nature Medicine 2010;16:232-236.
  4. Delaney C, Milano F, Cicconi L, et al., Infusion of a non-HLA-matched ex-vivo expanded cord blood progenitor cell product after intensive acute myeloid leukaemia chemotherapy: a phase 1 trial. The Lancet Haematology 2016;3:e330-e339.
  5. Bretscher MS and Raff MC, Mammalian plasma membranes. Nature 1975;258:43-49.
  6. Cuchiara ML, Coşkun S, Banda OA, et al., Bioactive poly(ethylene glycol) hydrogels to recapitulate the HSC niche and facilitate HSC expansion in culture. Biotechnology and Bioengineering 2016;113:870-881.
  7. Bai T, Li J, Sinclair A, et al., Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel. Nature Medicine 2019;25:1566-1575.