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Direct Reprogramming of Amniotic Cells into Endothelial Cells

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Perinatal Stem Cells

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Abstract

Organ regeneration promises unlimited access to replacement tissues. The current paradigm of organ regeneration requires transplantation of adult tissue-restricted stem and progenitor cells to repair the damaged organ. However, healing injured organs often leads to fibrosis with little recovery of function. An alternative approach is to harness the regenerative activity of microvascular endothelial cells (ECs) to support endogenous organ repair. Recent work demonstrates that organ regeneration can be directed by paracrine mediators, called “Angiocrine Factors,” elaborated by tissue-specific ECs to support stem and progenitor cells to directly induce organ regeneration without maladaptive fibrosis. Yet, the regenerative function and the repertoire of angiocrine factors elaborated by ECs depend upon the organ from which they originate.

New technologies have emerged to transcriptionally reprogram amniotic fluid cells (ACs) into generic “unspecified” ECs that acquire tissue-specific function promises a ready source of transplantable ECs to be used for organ regeneration. Generic AC-derived ECs can be induced to acquire organ-specific functions by a process of “in vivo education” wherein extravascular cues trigger transcriptional programs within engrafted ECs enabling them to acquire tissue-specific functions and to deploy angiocrine growth factors that drive organ repair without aberrant pro-fibrotic remodeling. Identifying tissue-specific transcription factors regulating tissue specification of EC is at the frontier of this new approach for organ regeneration.

The chapter is expected to overturn the scientific conceptualization of a monofunctional, inert, microvasculature by revealing a dynamic, tissue-specified role for ECs in organ repair that will enable therapeutic use of “educated,” tissue-specified ECs that home to their native injured organs and supply tissue-specific angiocrine signals to orchestrate organ regeneration.

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Notes

  1. 1.

    A cell specified autonomously will develop into a specific fate based upon cell-intrinsic properties that are cytoplasmic determinants with no regard to the environment the cell is in.

    A cell specified conditionally will develop into a specific fate based upon cell-extrinsic process that relies on cues and other surrounding cells or morphogen gradients.

    A cell specified syncytially will develop into a specific fate based upon a hybrid of the autonomous and conditional method involves the action of morphogen gradients within the syncytium that can influence nuclei in a concentration-dependent manner.

    A cell determined will develop into a specific cell types followed by differentiation.

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Author information

Authors and Affiliations

  1. Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10064, USA

    Koji Shido M.S., Ph.D., Joseph M. Scandura M.D., Ph.D. & Shahin Rafii M.D.

  2. Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10064, USA

    Venkat R. Pulijaal Ph.D.

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  1. Koji Shido M.S., Ph.D.
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  2. Joseph M. Scandura M.D., Ph.D.
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  3. Shahin Rafii M.D.
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  4. Venkat R. Pulijaal Ph.D.
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Editor information

Editors and Affiliations

  1. Wake Forest Baptist Medical Center, Institute for Regenerative Medicine, Winston-Salem, North Carolina, USA

    Anthony Atala

  2. Wake Forest Baptist Medical Center, Institute for Regenerative Medicine, Winston-Salem, North Carolina, USA

    Sean V. Murphy

Appendix: Material and Methods

Appendix: Material and Methods

1.1 Cell Culture

Culture Condition for Amniotic Cells (AFCs):

  • Amniotic Media (AM): Amnio-Max + Supplement (GIBCO) with 1X Pen/Strep (Invitrogen)

Differentiation of AFCs:

  • Transfected AFCs with lentiviral vectors

  • Culture media supplemented with Endothelial Growth Media (EM) in Medium 199 (Thermo Scientific), 15 % Fetal Bovine Serum (Omega Scientific), 20 mg/mL endothelial cell supplement (Hallway), 1 % antibiotics (Hallway), 20 units/mL heparin (Sigma), and where indicated, 5 mM SB431542 (Tocris)

  • Gelatin powder (J.T. Baker, Phillipsburg, NJ), 0.2 % in sterile water and stored at 4 °C

  • HEPES: 1 M HEPES made in sterile water, pH adjusted to 7.55 at room temperature

  • Bovine serum albumin

  • 500 mL filter system

1.2 Lentiviral Vectors and Transduction

Human amniotic fluid cells (AFCs) from second trimester amniocentesis are forced ectopic expression of transient Etv2/ER71 with concomitant Fli1/Erg1 using cloned human ER71, Erg-2, and Fli1 cDNAs into lentiviral vectors and TGFβ inhibitor, SB431542 [10]. Successful transduction specifies AFCs directly reprogrammed into naïve endothelial cells (ECs) [9].

Functionality of reprogrammed ECs assessed in vitro and in vivo models whether these ECs have acquired full angiogenic potential. A matrigel tube formation assay performed on 21-day-old ER71/Fli1 transduced ECs that were concurrently under TGFβ inhibition. Notably, ECs expressing ER71 and ER71/Fli1, but not naïve AFCs, were capable of forming tubes in vitro comparable to tubulogenesis observed by HUVECs. A second in vitro assay was then performed on ECs to demonstrate another EC attribute—Acetylated-LDL (Ac-LDL) uptake. Incubation of 21-day-old ECs with Ac-LDL showed significant accumulation of this lipoprotein similar to Ac-LDL uptake seen in HUVECs. GFP-labeled 21-day-old ECs were loaded into matrigel plugs supplemented with VEGF-A and FGF-2, and injected into immunocompromised NOD-SCIDIL2Rg−/− (NSG) mice for 2 weeks. Following intravital labeling of the vasculature by Isolectin, matrigel plugs were then removed for analysis. Although naïve AFCs failed to form any capillaries, 21-day-old ECs formed numerous functional vessels that anastomosed with host vasculature. Taken together, these data verify the notion that ER71 and Fli1, acting in concert with TGF-b inhibition, can reprogram mid-gestational AFCs into functionally viable VEGF-A-dependent proliferative ECs that are capable of developing bona fide functional blood vessels.

Multiple cDNAs: ER71, Erg-2, and Fli1: Clone into the pCCL-PGK lentivirus vector.

  • A triple Flag-tag: Subclone into the ER71 and Erg-2 constructs at the amino terminus, via Quick-Change Site Directed Mutagenesis Kit (Stratagene), then re-subclone Flag-tag ER71 into the pLVX-Tight-Puro vector (Clontech) and co-transduce with pLVX-Tet-Off vector

  • Lentiviruses: Generate by cotransfecting 15 mg of our gene of interest lentiviral ECtor, 3 mg of pENV/VSV-G, 5 mg of pRRE, and 2.5 mg of pRSV-REV in 293 T cells (passage 8–10; subconfluent, 100 mm dish) by the calcium precipitation method

  • Harvesting Supernatants: Collect supernatants within 40 to 64 h after transfection [174], then concentrate by Lenti-X concentrator (Clontech) and obtain viral titers determined by using the Lenti-X p24 Rapid Titer kit (Clontech).

  • Recommended use to transduce AFCs: MOI = 1

1.3 Matrigel™ Plug and In Vitro Assays

Mix AFCs infected with ETS factors transduced with GFP-lentivirus with Matrigel (BD), 100 ng/mL of VEGF-A, and 50 ng/mL of FGF-2, and subcutaneously implant at the flanks of NOD-SCID gamma (NSG) mice (Jackson Laboratories, Bar Harbor, ME). After 2 weeks, inject isolectin conjugated with Alexa 568 (Invitrogen) (2 mg/kg) and sacrifice to harvest the tissue. Fix the tissue in 4 % paraformaldehyde, followed by 48 h saturation in 30 % sucrose. Prepare 20 μm cryosections and counterstain with Hoechst 33342. Enumerate the number of isolectin-positive functional vessels.

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Shido, K., Scandura, J.M., Rafii, S., Pulijaal, V.R. (2014). Direct Reprogramming of Amniotic Cells into Endothelial Cells. In: Atala, A., Murphy, S. (eds) Perinatal Stem Cells. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1118-9_7

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