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Eco matters; In & Out

Citation: Editorial. Eco matters; In & Out. J Stem Cells Regen Med 2016; 12(2) :52-53

In vitro culture of cells and tissues were undertaken to understand the intricacies of cellular biology per se until recently, when such in vitro grown cells and tissues have started evolving as tools of regenerative medicine. Only after such clinical applications of in vitro cultured cells and tissues became a possibility, various criteria about the compatibility of in vitro environments to the cells and tissues have gained significant attention.

Among the in vitro cultured cells, chondrocytes pop up as one of the most approved cell-based products by regulatory authorities of many countries including the USA, Europe and Japan [1]. In this procedure, it has been reported by several studies that human articular chondrocytes (HACs) when cultured as monolayer, they tend to de-differentiate [2] whereas 3D cultures help to establish the native hyaline phenotype [3]. Variations of such significance in the in vitro behaviour of other cell types have also been reported in literature [4-9] which clearly demonstrate that in vitro environments play a crucial role in maintaining cells with the proper phenotype and functionality for clinical transplantation.

Another major factor which needs to be studied thoroughly iscellular senescence in the in vitro environment. Though cells derived from older individuals may share cellular and molecular phenotypes with in vitro senescent cells, in vitro acquired cellular senescence is a proven phenomenon [10]. While the 'Hayflick limit' specifies a particular number of maximum population doubling for a specific cell type in vitro, the same cell type in vivo may undergo more than the Hayflick limit specified population doubling in a lifetime without senescence [11] creating the need for improvising current in vitro cell culture techniques to reflect what occurs in vivo.

Given the above background, the goal of in vitro cell and tissue engineering is to grow cells with optimal functionality while simultaneously preventing uncontrolled or premature differentiation and the onset of senescence [12]. Stressing the importance of in vitro environments, even regulatory agencies like the US-FDA use in vitro manipulation as a gauge to classify cell therapies[13].

In this issue, a diverse assortment of articles ranging from the use of scaffolds for in vitro culture by Gomathysankar et al [14] to employing tools for in vivo transplantation of cells by Maiti et al [15]and Fauzi et al [16] have been published. During regenerative medicine applications, cells undergo several transitions across environments, starting with an in vivo to in vitro transition when harvested from the body and subjected to culture-expansion or tissue engineering kind of processing and then a reversal back to an in vivo environment. While the factors and materials employed in the in vitro eco-system are known, their effects are known though to an extent, some of their implications still remain unknown and the mechanisms of those implications are largely obscure [17-19]. These bunch of changes in the whole eco-system inside-out and vice versa need a meticulous and flawless assessment which is indispensable in improvising the clinical outcome of regenerative medicine applications.


  1. Yanoa K, Watanabe N, Tsuyuki K, Ikawa T, Kasanuki H, Yamato M. Regulatory approval for autologous human cells and tissue products in the United States, the European Union, and Japan. Regenerative Therapy 2015; 1: 45-56
  2. Schnabel M, Marlovits S, Eckhoff G, Fichtel I, Gotzen L, Vécsei V, Schlegel J. Dedifferentiation-associated changes in morphology and gene expression in primary human articular chondrocytes in cell culture. Osteoarthritis Cartilage. 2002;10(1):62-70.
  3. Caron MM, Emans PJ, Coolsen MM, Voss L, Surtel DA, Cremers A, van Rhijn LW, Welting TJ. Redifferentiation of dedifferentiated human articular chondrocytes: comparison of 2D and 3D cultures. Osteoarthritis Cartilage. 2012;20(10):1170-8.
  4. Hsiong SX, Carampin P, Kong HJ, Lee KY, Mooney DJ. Differentiation stage alters matrix control of stem cells. J Biomed Mater Res A. 2008; 85(1):145-56. Erratum in: J Biomed Mater Res A. 2008;87(1):282.
  5. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4):677-89.
  6. Huang C, Dai J, Zhang XA. Environmental physical cues determine the lineage specification of mesenchymal stem cells. Biochim Biophys Acta. 2015;1850(6):1261-6.
  7. Lee J, Abdeen AA, Kilian KA. Rewiring mesenchymal stem cell lineage specification by switching the biophysical microenvironment. Sci Rep. 2014;4:5188.
  8. Evans ND, Minelli C, Gentleman E, LaPointe V, Patankar SN, Kallivretaki M, Chen X, Roberts CJ, Stevens MM. Substrate stiffness affects early differentiation events in embryonic stem cells. Eur Cell Mater. 2009;18:1-13;
  9. Jaramillo M, Singh SS, Velankar S, Kumta PN, Banerjee I. Inducing endoderm differentiation by modulating mechanical properties of soft substrates. J Tissue Eng Regen Med. 2015;9(1):1-12.
  10. Faraonio R, Pane F, Intrieri M, Russo T, Cimino F. In vitro acquired cellular senescence and aging-specific phenotype can be distinguished on the basis of specific mRNA expression. Cell Death Differ. 2002;9(8):862-4.
  11. Rubin H. Promise and problems in relating cellular senescence in vitro to aging in vivo. Arch Gerontol Geriatr. 2002;34(3):275-86.
  12. Brown PT, Handorf AM, Jeon WB, Li WJ. Stem cell-based tissue engineering approaches for musculoskeletal regeneration. Curr Pharm Des. 2013;19(19):3429-45.
  13. Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance [Internet]. U.S. Food and Drug Administration [cited 2016 Nov 24]. Available from:
  14. Gomathysankar S, Halim AS, Yaacob NS, Noor NM, Mohamed M. Compatibility of Porous Chitosan Scaffold with the Attachment and Proliferation of human Adipose-Derived Stem Cells In vitro. J Stem Cells Regen Med 2016; 12 (2):79-86.
  15. Maiti SK, Ninu AR, Sangeetha P, Mathew DD, Tamilmahan P, Kritaniya D, Kumar N and Hescheler J. Mesenchymal stem cells-seeded bio-ceramic construct for bone regeneration in large critical-size bone defect in rabbit. J Stem Cells Regen Med 2016;12 (2):87-99.
  16. Fauzi AA, Suroto NS, Bajamal AH, Machfoed MH. Intraventricular Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells via Ommaya Reservoir in Persistent Vegetative State Patients after Haemorrhagic Stroke: Report of Two Cases & Review of the Literature. J Stem Cells Regen Med 2016; 12 (2):100-104.
  17. Snykers S, De Kock J, Rogiers V, Vanhaecke T. In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells. 2009;27(3):577-605
  18. Moore KA, Ema H, Lemischka IR. In vitro maintenance of highly purified, transplantable hematopoietic stem cells. Blood. 1997;89(12):4337-47.
  19. Lv H, Li L, Sun M, Zhang Y, Chen L, Rong Y, Li Y. Mechanism of regulation ofstem cell differentiation by matrix stiffness. Stem Cell Res Ther. 2015;6:103.