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Biomimicry in mending the broken heart; Will hypoxia and pulsatile flow play Cupids?

Oxygen, the most important cellular nutrition, is delivered through a pulsatile blood flow in vertebrates to the tissues and cells in vivo, wherein the oxygen concentration, its availability gradient between systolic and diastolic phase of cardiac activity differ between organs. In the in vitro conditions, manipulation of oxygen availability to the cells under culture have yielded varying behaviours depending on the type of cells, their stemness etc. [1-5]. Adding a pulsatile component to such in vitro conditions has shown the cells behaving in different manners in such environments [6,7]. While our earlier editorial titled “Hypoxia is no hype: Perspectives across Phylogeny, Stem Cell differentiation & Geochemistry” [8]  had described the importance of hypoxia in stem cell-based research wherein stemness is preserved more efficiently under hypoxia [4,5], an article in this issue titled “Comparing the in vivo and in vitro effects of hypoxia (3% O2) on directly derived cells from murine cardiac explants versus murine cardiosphere derived cells” [9]  has further intrigued us to analyse this phenomenon.

The pumping chamber of the heart, the left ventricle is supplied mostly during the diastole when it relaxes, whilst the other tissues get the supply during systole. The gradient of oxygen concentration that occurs between the peak vs the low availability, is the highest in cardiac tissue, while lowest in the periphery [10]. Hence, the effects of fluid dynamics and oxygen concentration may have a significantly higher influence on culture of cardiac tissue-derived cells and the application of this phenomena on cells, which are tailored to address myocardial regeneration. Several attempts are being made to employ hypoxic pre-conditioning to improve the therapeutic potential of cardiac tissue-derived stem and progenitor cells with studies reporting significant enhancement in the anti-apoptotic and migratory potential of these cells in vitro, and better survival and cardiac function after in vivo transplantation. Amirrasouli et al [9] report their findings on comparing the effect of hypoxic preconditioning on pro-angiogenic potential of cardiac tissue explant-derived cell (EDCs) and cardiosphere-derived cells (CDCs). Since they rationalize that culture of CDC and Csph formation is 'time consuming, expensive and not always successful', their findings support their rationale, wherein hypoxic preconditioning of the EDCs has shown to enhance cell growth, viability and expression of stem cell and pro-angiogenic markers more than the CDCs thus giving rise to a therapeutically valuable cell population in EDCs.

We intend to point out the importance of hypoxic pre-conditioning during the in vitro processing of cells aimed at treating cardiac diseases as the myocardial cells are greatly influenced by hypoxic conditions. Adding a pulsatile component to hypoxia[11] or delivering the oxygen in a manner resembling the in vivo variabilities produced by a pulsatile blood flow are worth considering an in-depth exploration. If such systems could also mimick the heart rate of the particular individual whose cells are subjected to in vitro processing, it could bring the in vitro systems much closer to the individual’s physiology as the oxygen delivery to cardiac tissues vary according to heart rate[12]. Biomimicry is an indispensable component to several inventions in Biology; it is the biomechanical force produced by the first heartbeat that triggers the development of hematopoietic stem cells (HSC) themselves[13,14].


  1. Wagner BA, Venkataraman S, Buettner GR. The rate of oxygen utilization by cells. Free Radic Biol Med. 2011 Aug 1;51(3):700-12. Li TS, Cheng K, Malliaras K, Matsushita N, Sun B, Marbán L, Zhang Y, Marbán E.
  2. Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovasc Res. 2011 Jan 1;89(1):157-65.
  3. Chen J, Yang Y, Shen L, Ding W, Chen X, Wu E, Cai K, Wang G. Hypoxic Preconditioning Augments the Therapeutic Efficacy of Bone Marrow Stromal Cells in a Rat Ischemic Stroke Model. Cell Mol Neurobiol. 2017 Aug;37(6):1115-1129.
  4. Tang YL, Zhu W, Cheng M, Chen L, Zhang J, Sun T, Kishore R, Phillips MI, Losordo DW, Qin G. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ Res. 2009 May 22;104(10):1209-16.
  5. van der Sanden B, Dhobb M, Berger F, Wion D. Optimizing stem cell culture. J Cell Biochem. 2010 Nov 1;111(4):801-7. Peng X, Recchia FA, Byrne BJ, Wittstein IS, Ziegelstein RC, Kass DA. In vitro
  6. system to study realistic pulsatile flow and stretch signaling in cultured vascular cells. Am J Physiol Cell Physiol. 2000 Sep;279(3):C797-805.
  7. Smith Q, Gerecht S. Going with the flow: microfluidic platforms in vascular tissue engineering. Curr Opin Chem Eng. 2014 Feb; 3:42-50.
  8. Hypoxia is no hype: Perspectives across Phylogeny, Stem Cell differentiation & Geochemistry. J Stem Cells Regen Med. 2015 May 30;11(1):1.
  9. Amirrasouli MM, Shamsara M. Comparing the in vivo and in vitro effects of hypoxia (3% O2) on directly derived cells from murine cardiac explants versus murine cardiosphere derived cells. J Stem Cells Regen Med 2017 Sep. [Epub ahead of print]
  10. Fukuta H, Little WC. The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin. 2008 Jan;4(1):1-11.
  11. Correia C, Serra M, Espinha N, Sousa M, Brito C, Burkert K, Zheng Y, Hescheler J, Carrondo MJ, Sarić T, Alves PM. Combining hypoxia and bioreactor hydrodynamics boosts induced pluripotent stem cell differentiation towards cardiomyocytes. Stem Cell Rev. 2014 Dec;10(6):786-801.
  12. Tanaka N, Nozawa T, Yasumura Y, Futaki S, Hiramori K, Suga H. Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart. Jpn J Physiol. 1990;40(4):503-21.
  13. ­Adamo L, Naveiras O, Wenzel PL, McKinney-Freeman S, Mack PJ, Gracia-Sancho J,Suchy-Dicey A, Yoshimoto M, Lensch MW, Yoder MC, García-Cardeña G, Daley GQ. Biomechanical forces promote embryonic haematopoiesis. Nature. 2009 Jun 25;459(7250):1131-5.
  14. North TE, Goessling W, Peeters M, Li P, Ceol C, Lord AM, Weber GJ, Harris J,Cutting CC, Huang P, Dzierzak E, Zon LI. Hematopoietic stem cell development is dependent on blood flow. Cell. 2009 May 15;137(4):736-48.
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