Substrate stiffness directs the phenotype and polarization state of cord blood derived macrophages
Open accessAbstract
Cord blood (CB) mononuclear cell populations have demonstrated significant promise in biomaterials-based regenerative therapies; however, the contributions of monocyte and macrophage subpopulations towards proper tissue healing and regeneration are not well understood, and the phenotypic responses of macrophage to microenvironmental cues have not been well-studied. In this work, we evaluated the effects of cytokine stimulation and altered substrate stiffness. Macrophage derived from CB CD14+ monocytes adopted distinct inflammatory (M1) and anti-inflammatory (M2a and M2c) phenotypes in response to cytokine stimulation (M1: lipopolysaccharide (LPS) and interferon (IFN-γ); M2a: interleukin (IL)-4 and IL-13; M2c: IL-10) as determined through expression of relevant cell surface markers and growth factors. Cytokine-induced macrophage readily altered their phenotypes upon sequential administration of different cytokine cocktails. The impact of substrate stiffness on macrophage phenotype was evaluated by seeding CB-derived macrophage on 3wt%, 6wt%, and 14wt% poly(ethylene glycol)-based hydrogels, which exhibited swollen shear moduli of 0.1, 3.4, and 10.3 kPa, respectively. Surface marker expression and cytokine production varied depending on modulus, with anti-inflammatory phenotypes increasing with elevated substrate stiffness. Integration of specific hydrogel moduli and cytokine cocktail treatments resulted in the differential regulation of macrophage phenotypic biomarkers. These data suggest that CB-derived macrophages exhibit predictable behaviors that can be directed and finely tuned by combinatorial modulation of substrate physical properties and cytokine profiles.
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Only a limited number of studies have investigated the effects of stiffness on human primary macrophages.
“Only a limited number of studies have investigated the effects of stiffness on human primary macrophages.”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [24]
The Introduction (page not provided) says that substrate stiffness effects on cord-blood-derived macrophages have not been well characterized, and it identifies earlier work on human peripheral-blood-derived macrophages. That supports a research gap for cord-blood-derived cells, but not the broader claim that only a limited number of studies have examined human primary macrophages generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMacrophages attaching to soft materials exhibit reduced activation into profibrotic M2 macrophages compared to those grown on stiffer substrates.
“In general, macrophages attaching to soft materials exhibit reduced activation into profibrotic M2 macrophages compared to those grown on stiffer substrates (44–48).”
From Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy (2024) · cites this paper as [48]
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- Authors
- Scott, R. A., Kiick, K. L., & Akins, R. E.
- Affiliations
- Alfred I. duPont Hospital for Children (US)
- Delaware Biotechnology Institute (US)
- Corresponding author
- Akins, Robert E.
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 122
- Pages
- 220-235
- ISSN
- 1742-7061 (ISSN-L)
- PMC
- PMC7904389
- OpenAlex
- W3117600942
- Cited by
- 43
- References
- 72
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 12 · 2023: 4 · 2022: 4 · 2021: 6
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences
- National Heart, Lung, and Blood Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- substrate stiffness, macrophage polarization, M1/M2 macrophage phenotype, cytokine induction, poly(ethylene glycol) hydrogels, hydrogel modulus, CD14+ monocytes, lipopolysaccharide, interferon-gamma, IL-4, IL-13, IL-10, regenerative therapy, biomaterials
- MeSH terms
- Cell Differentiation, Fetal Blood, Macrophages, Phenotype, Cytokines
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